chr20-10413405-T-C

Position:

• chr20-10413405-T-C

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2 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 (★★).

• 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:20
• Conservation: PhyloP100: 3.44

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 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 14 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• 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 [Likely_pathogenic]. Clinvar id is 5309.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr20-10413405-T-C is described in Lovd as [Pathogenic]. Variant chr20-10413405-T-C is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MKKS	NM_170784.3	c.110A>G	p.Tyr37Cys	missense_variant	3/6	ENST00000347364.7	NP_740754.1
MKKS	NM_018848.3	c.110A>G	p.Tyr37Cys	missense_variant	3/6		NP_061336.1
MKKS	NR_072977.2	n.347-4602A>G		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MKKS	ENST00000347364.7	c.110A>G	p.Tyr37Cys	missense_variant	3/6	1	NM_170784.3	ENSP00000246062.4
MKKS	ENST00000399054.6	c.110A>G	p.Tyr37Cys	missense_variant	3/6	1		ENSP00000382008.2
MKKS	ENST00000651692.1	c.110A>G	p.Tyr37Cys	missense_variant	4/7			ENSP00000498849.1
MKKS	ENST00000652676.1	n.458+391A>G		intron_variant

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

GnomAD3 exomes AF: 0.0000677 AC: 17 AN: 251046 Hom.: 0 AF XY: 0.0000590 AC XY: 8 AN XY: 135656

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 SAS exome AF: 0.0000654

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

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000928

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000212

Gnomad4 OTH exome AF: 0.0000663

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

Gnomad4 AFR AF: 0.0000965

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000162

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000127 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:20

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:8

Pathogenic, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	Oct 23, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Feb 13, 2015	- -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	May 08, 2024	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) -
Pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Clinical Genetics Laboratory, Skane University Hospital Lund	Jul 04, 2023	- -

Bardet-Biedl syndrome 6 Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	3billion	Jan 03, 2022	Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000005309, PS1_S). Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID: 18094050, , PS3_S). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.87, PP3_P). It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.000071, PM2_M). The variant has been reported to be in trans as homozygous in at least one similarly affected unrelated individual (PMID: 10973251, PM3_P). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Feb 23, 2024	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Sep 21, 2001	- -
Pathogenic, criteria provided, single submitter	clinical testing	MGZ Medical Genetics Center	Jun 13, 2022	- -

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

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Mar 26, 2022

- -

MKKS-related disorder Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 25, 2024

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

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 27, 2017

- -

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

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 30, 2023

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). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae 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

Pathogenic, no assertion criteria provided

clinical testing

Sydney Genome Diagnostics, Children's Hospital Westmead

Jul 26, 2016

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

Pathogenic, no assertion criteria provided

literature only

OMIM

Sep 21, 2001

- -

Retinal dystrophy Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Blueprint Genetics

Nov 16, 2018

- -

Bardet-Biedl syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

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

Mar 29, 2022

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 v4.3

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;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;D
MetaSVM	Uncertain	0.48	D
MutationAssessor	Pathogenic	2.9	M;M
PrimateAI	Uncertain	0.56	T
PROVEAN	Pathogenic	-5.2	D;D
REVEL	Pathogenic	0.87
Sift	Uncertain	0.0010	D;D
Sift4G	Pathogenic	0.0010	D;D
Polyphen		1.0	D;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

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

Publications

LitVar

Other links and lift over

dbSNP: rs74315396; hg19: chr20-10394053;