20-10413405-T-C

Variant names:

• chr20-10413405-T-C
• rs74315396
• NM_170784.3:c.110A>G

Variant summary

Our verdict is Pathogenic. The variant received 14 ACMG points: 14P and 0B. PM1 PP3_Strong PP5_Very_Strong

The NM_170784.3(MKKS):​c.110A>G​(p.Tyr37Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000164 in 1,613,034 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Y37H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00011 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00017 (0 hom.)
• Consequence: MKKS NM_170784.3 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:22
• Conservation: PhyloP100: 3.44
• Publications: 15 publications found

Genes affected

MKKS (HGNC:7108): (MKKS centrosomal shuttling protein) This gene encodes a protein which shares sequence similarity with other members of the type II chaperonin family. The encoded protein is a centrosome-shuttling protein and plays an important role in cytokinesis. This protein also interacts with other type II chaperonin members to form a complex known as the BBSome, which involves ciliary membrane biogenesis. This protein is encoded by a downstream open reading frame (dORF). Several upstream open reading frames (uORFs) have been identified, which repress the translation of the dORF, and two of which can encode small mitochondrial membrane proteins. Mutations in this gene have been observed in patients with Bardet-Biedl syndrome type 6, also known as McKusick-Kaufman syndrome. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Feb 2023]

MKKS Gene-Disease associations (from GenCC):

• McKusick-Kaufman syndrome

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), G2P, Orphanet
• Bardet-Biedl syndrome 6

  Inheritance: AR Classification: STRONG Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
• Bardet-Biedl syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000285508 (HGNC:):

ACMG classification

Our verdict: Pathogenic. The variant received 14 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 3 uncertain in NM_170784.3
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.952
• PP5: Variant 20-10413405-T-C is Pathogenic according to our data. Variant chr20-10413405-T-C is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 5309.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_170784.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MKKS	NM_170784.3	MANE Select	c.110A>G	p.Tyr37Cys	missense	Exon 3 of 6	NP_740754.1
	MKKS	NM_018848.3		c.110A>G	p.Tyr37Cys	missense	Exon 3 of 6	NP_061336.1
	MKKS	NR_072977.2		n.347-4602A>G		intron	N/A

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MKKS	ENST00000347364.7	TSL:1 MANE Select	c.110A>G	p.Tyr37Cys	missense	Exon 3 of 6	ENSP00000246062.4
	MKKS	ENST00000399054.6	TSL:1	c.110A>G	p.Tyr37Cys	missense	Exon 3 of 6	ENSP00000382008.2
	MKKS	ENST00000651692.1		c.110A>G	p.Tyr37Cys	missense	Exon 4 of 7	ENSP00000498849.1

Frequencies

GnomAD3 genomes AF: 0.000105 AC: 16 AN: 152186 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000965

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000162

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000677 AC: 17 AN: 251046 AF XY: 0.0000590

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000132

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000170 AC: 249 AN: 1460848 Hom.: 0 Cov.: 32 AF XY: 0.000168 AC XY: 122 AN XY: 726520

African (AFR) AF: 0.0000299 AC: 1 AN: 33458

American (AMR) AF: 0.00 AC: 0 AN: 44694

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26126

East Asian (EAS) AF: 0.00 AC: 0 AN: 39676

South Asian (SAS) AF: 0.0000928 AC: 8 AN: 86252

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53406

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.000212 AC: 236 AN: 1111116

Other (OTH) AF: 0.0000663 AC: 4 AN: 60354

GnomAD4 genome AF: 0.000105 AC: 16 AN: 152186 Hom.: 0 Cov.: 32 AF XY: 0.0000672 AC XY: 5 AN XY: 74362

African (AFR) AF: 0.0000965 AC: 4 AN: 41446

American (AMR) AF: 0.00 AC: 0 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5200

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000162 AC: 11 AN: 68032

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.0000974 Hom.: 0

Bravo AF: 0.0000680

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.0000576 AC: 7

EpiCase AF: 0.000218

EpiControl AF: 0.000119

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:22

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:8

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

Clinical Genetics, Academic Medical Center

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

Jul 04, 2023

Clinical Genetics Laboratory, Skane University Hospital Lund

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

Feb 13, 2015

Eurofins Ntd Llc (ga)

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Oct 23, 2020

Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

May 08, 2024

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Published functional studies demonstrate a damaging effect (PMID: 18094050, 20498079); Identified in patients with MKKS-related ciliopathy referred for genetic testing at GeneDx and in published literature (PMID: 35886001, 10973251, 20177705, 25982971, 10802661); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 10802661, 18094050, 22446187, 20177705, 25982971, 11673413, 21044901, 12107442, 34426522, 34929400, 20498079, 35112343, 10973251, 35886001, 31964843)

Bardet-Biedl syndrome 6 Pathogenic:4

Jun 13, 2022

MGZ Medical Genetics Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Sep 21, 2001

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

Jun 21, 2023

3billion

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.007%). Predicted Consequence/Location: Protein truncation variants are a common disease-causing mechanism. Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID: 18094050). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.87; 3Cnet: 0.24). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000005309 /PMID: 10802661 /3billion dataset). The variant has been reported to be in trans with a pathogenic variant as either compound heterozygous or homozygous in at least one similarly affected unrelated individual (PMID: 10973251). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.

Feb 23, 2024

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

McKusick-Kaufman syndrome;C1858054:Bardet-Biedl syndrome 6 Pathogenic:1

Jun 17, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

MKKS-related disorder Pathogenic:1

Jun 25, 2024

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The MKKS c.110A>G variant is predicted to result in the amino acid substitution p.Tyr37Cys. This variant has been reported to be causative for Bardet-Biedl syndrome and McKusick-Kaufman syndrome (Katsanis et al. 2001. PubMed ID: 11567139; Stone et al. 2000. PubMed ID: 10802661; Muller et al. 2010. PubMed ID: 20177705; Zaghloul et al. 2010. PubMed ID: 20498079; Scheidecker et al. 2015. PubMed ID: 25982971). This variant is reported in 0.014% of alleles in individuals of European (Non-Finnish) descent in gnomAD. This variant is interpreted as pathogenic.

Inborn genetic diseases Pathogenic:1

Nov 27, 2017

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Bardet-Biedl syndrome;C0948368:McKusick-Kaufman syndrome Pathogenic:1

Sep 29, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 37 of the MKKS protein (p.Tyr37Cys). This variant is present in population databases (rs74315396, gnomAD 0.01%). This missense change has been observed in individual(s) with Bardet-Biedl syndrome (PMID: 10802661). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 5309). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt MKKS protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects MKKS function (PMID: 18094050, 20498079). For these reasons, this variant has been classified as Pathogenic.

Nephronophthisis Pathogenic:1

Jul 26, 2016

Sydney Genome Diagnostics, Children's Hospital Westmead

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

This patient is heterozygous for the c.110A>G p.(Tyr37Cys) variant in the MKKS gene. This variant is listed in the ExAC database (http://exac.broadinstitute.org) with a very low allele frequency of 0.0058% (27 out of 121,342 alleles). It has been reported in the homozygous state in a patient with Bardet-Biedl syndrome (Bardet-Biedl syndrome) and in a compound heterozygous state with a patient with McKusick-Kaufman syndrome (Katsanis et al. 2000 Nat Genet 26: 67-70; Stone et al. 2000 Nat Genet 25: 79-82). In vitro studies found that the p.Tyr37Cys substitution led to decreased protein levels and resulted in structual instability (Hirayama et al. 2008 Mol Biol Cell 19: 899-911). This variant is considered to be pathogenic according to the ACMG guidelines.

McKusick-Kaufman syndrome Pathogenic:1

Sep 21, 2001

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

Syndromic inherited retinal disease Pathogenic:1

Oct 01, 2024

Lab De Baere, Eye and Developmental Genetics Lab, Ghent University

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

ACMG/AMP guidelines: PM2, PS3, PM3_2

MKKS-related ciliopathy Pathogenic:1

Nov 28, 2024

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is classified as Pathogenic. Evidence in support of pathogenic classification: Variant is present in gnomAD <0.01 for a recessive condition (v4: 265 heterozygote(s), 0 homozygote(s)); This variant has very strong previous evidence of pathogenicity in unrelated individuals. This variant has been classified as pathogenic by clinical laboratories in ClinVar; Missense variant consistently predicted to be damaging by in silico tool or highly conserved with a major amino acid change; Very strong and specific phenotype match for this individual. Additional information: Variant is predicted to result in a missense amino acid change from tyrosine to cysteine; This variant is heterozygous; This gene is associated with autosomal recessive disease; Loss of function is a known mechanism of disease in this gene and is associated with MKKS-related ciliopathy (MONDO:1040050); This variant has been shown to be paternally inherited (by trio analysis).

Retinal dystrophy Pathogenic:1

Nov 16, 2018

Blueprint Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Bardet-Biedl syndrome Pathogenic:1

Mar 29, 2022

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: MKKS c.110A>G (p.Tyr37Cys) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 6.8e-05 in 251046 control chromosomes (gnomAD). This frequency is not higher than expected for a pathogenic variant in MKKS causing Bardet-Biedl Syndrome (6.8e-05 vs 0.00076), allowing no conclusion about variant significance. c.110A>G has been reported in the literature in multiple individuals affected with Bardet-Biedl Syndrome (e.g. Katsanis_2000, Feuillan_2011, Zaghloul_2010) and McKusick-Kaufman syndrom (e.g. Stone_2000), including homozygotes. These data indicate that the variant is very likely to be associated with disease. At least two functional studies report experimental evidence evaluating an impact on protein function and this variant results in protein rapid degradation, increased insolubility of MKKS protein and forming partially immobilized structures at the centrosome (Hirayama_2008, Zaghloul_2010). Eight ClinVar submitters have assessed the variant since 2014: all eight classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Pathogenic	0.23	D
BayesDel_noAF	Pathogenic	0.32
CADD	Uncertain	26
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.91	D
Eigen	Pathogenic	0.72
Eigen_PC	Pathogenic	0.70
FATHMM_MKL	Uncertain	0.79	D
LIST_S2	Uncertain	0.91	D
M_CAP	Uncertain	0.087	D
MetaRNN	Pathogenic	0.95	D
MetaSVM	Uncertain	0.48	D
MutationAssessor	Pathogenic	2.9	M
PhyloP100		3.4
PrimateAI	Uncertain	0.56	T
PROVEAN	Pathogenic	-5.2	D
REVEL	Pathogenic	0.87
Sift	Uncertain	0.0010	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.91
MVP		0.90
MPC		0.58
ClinPred		0.81	D
GERP RS		6.1
Varity_R		0.57
gMVP		0.69
Mutation Taster		=11/89	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs74315396; hg19: chr20-10394053;