20-10412685-A-G

Position:

chr20-10412685-A-G

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2PP3_StrongPP5_Very_Strong

The NM_170784.3(MKKS):c.830T>C(p.Leu277Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000121 in 1,614,076 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 0.000059 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00013 ( 0 hom. )

Consequence

MKKS
NM_170784.3 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:12U:1

Conservation

PhyloP100: 8.55

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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, 0.951

PP5

Variant 20-10412685-A-G is Pathogenic according to our data. Variant chr20-10412685-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 5314.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr20-10412685-A-G is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MKKS	NM_170784.3 link	c.830T>C	p.Leu277Pro	missense_variant	3/6	ENST00000347364.7	NP_740754.1	Q9NPJ1B7Z3W9
MKKS	NM_018848.3 link	c.830T>C	p.Leu277Pro	missense_variant	3/6		NP_061336.1	Q9NPJ1B7Z3W9
MKKS	NR_072977.2 link	n.347-3882T>C		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
MKKS	ENST00000347364.7 link	c.830T>C	p.Leu277Pro	missense_variant	3/6	1	NM_170784.3	ENSP00000246062.4	Q9NPJ1
MKKS	ENST00000399054.6 link	c.830T>C	p.Leu277Pro	missense_variant	3/6	1		ENSP00000382008.2	Q9NPJ1
MKKS	ENST00000651692.1 link	c.830T>C	p.Leu277Pro	missense_variant	4/7			ENSP00000498849.1	Q9NPJ1
MKKS	ENST00000652676.1 link	n.474T>C		non_coding_transcript_exon_variant	4/7

Frequencies

GnomAD3 genomes

AF:

0.0000591

AC:

AN:

152210

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000118

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000637

AC:

AN:

251158

Hom.:

AF XY:

0.0000516

AC XY:

AN XY:

135730

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000868

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000969

Gnomad OTH exome

AF:

0.000327

GnomAD4 exome

AF:

0.000128

AC:

187

AN:

1461866

Hom.:

Cov.:

AF XY:

0.000118

AC XY:

AN XY:

727234

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.0000894

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000160

Gnomad4 OTH exome

AF:

0.0000662

GnomAD4 genome

AF:

0.0000591

AC:

AN:

152210

Hom.:

Cov.:

AF XY:

0.0000403

AC XY:

AN XY:

74352

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.0000655

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000118

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000213

Hom.:

Bravo

AF:

0.0000567

ExAC

AF:

0.0000412

AC:

EpiCase

AF:

0.000164

EpiControl

AF:

0.000119

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:12Uncertain:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:4Uncertain:1

Likely pathogenic, no assertion criteria provided	research	Gharavi Laboratory, Columbia University	Sep 16, 2018	- -
Likely pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jan 09, 2025	Published functional studies demonstrate a damaging effect (PMID: 20498079, 20080638); Missense variants in this gene are a common cause of disease and they are underrepresented in the general population; 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: 30586318, 20498079, 20080638, 11673413, 26900326, 15637713, 31964843, 37217489, 37734845, 22446187, 10973251, 21157496) -
Likely pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Uncertain significance, flagged submission	clinical testing	Eurofins Ntd Llc (ga)	Jan 21, 2015	- -

Bardet-Biedl syndrome 6

Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	OMIM	Feb 01, 2005	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 27, 2024	- -

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

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

May 28, 2024

- -

MKKS-related disorder

Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 22, 2024

The MKKS c.830T>C variant is predicted to result in the amino acid substitution p.Leu277Pro. This variant has been reported in the compound heterozygous state in at least one individual affected with Bardet-Biedl syndrome, and segregated with disease in the family (Katsanis et al. 2000. PubMed ID: 10973251; Moore et al. 2005. PubMed ID: 15637713). Functional studies revealed that this variant causes disruption of the MKKS-BBS12 interaction and could not rescue the morphant phenotype in zebrafish (Seo et al. 2010. PubMed ID: 20080638; Zaghloul et al. 2010. PubMed ID: 20498079, Supplementary Table 5; Hulleman et al. 2016. PubMed ID: 26900326). At PreventionGenetics, we identified this variant in the heterozygous state, along with a second heterozygous pathogenic variant, in an affected patient (internal data). Based on these observations, this variant is classified as pathogenic. -

Inborn genetic diseases

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 22, 2017

- -

Bardet-Biedl syndrome;C0948368:McKusick-Kaufman syndrome

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 21, 2024

This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 277 of the MKKS protein (p.Leu277Pro). This variant is present in population databases (rs74315398, gnomAD 0.009%). This missense change has been observed in individual(s) with Bardet-Biedl syndrome (PMID: 10973251). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 5314). 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 not expected to disrupt MKKS protein function with a negative predictive value of 80%. Experimental studies have shown that this missense change affects MKKS function (PMID: 20498079, 22446187). For these reasons, this variant has been classified as Pathogenic. -

McKusick-Kaufman syndrome

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

research

Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center

Mar 17, 2024

- -

Bardet-Biedl syndrome

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

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

Apr 14, 2023

Variant summary: MKKS c.830T>C (p.Leu277Pro) 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 6.4e-05 in 251158 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in MKKS causing Bardet-Biedl Syndrome (6.4e-05 vs 0.00076), allowing no conclusion about variant significance. c.830T>C has been reported in the literature in both compound heterozygous and homozygous individuals affected with Bardet-Biedl Syndrome and has been reported to segregate with disease in related individuals (e.g., Katsanis_2000, Pereiro_2011, Groopman_2019). These data indicate that the variant is likely to be associated with disease. Several publications report experimental evidence evaluating an impact on protein function, finding that the variant behaved a a null allele in a zebrafish model of gastrulation phenotypes (Zaghloul_2010) and greatly disrupted MKKS protein interactions (e.g., Rachel_2012, Seo_1010). Five ClinVar submitters (evaluation after 2014) have cited the variant with conflicting assessments; four submitters classified the variant as pathogenic/likely pathogenic, and one classified it as uncertain significance. Based on the evidence outlined above, the variant was classified as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.63

BayesDel_addAF

Pathogenic

0.27

BayesDel_noAF

Pathogenic

0.35

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.88

D;D

Eigen

Pathogenic

0.77

Eigen_PC

Pathogenic

0.78

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Benign

0.74

.;T

M_CAP

Uncertain

0.11

MetaRNN

Pathogenic

0.95

D;D

MetaSVM

Uncertain

0.23

MutationAssessor

Uncertain

2.7

M;M

PrimateAI

Uncertain

0.50

PROVEAN

Uncertain

-3.1

D;D

REVEL

Pathogenic

0.82

Sift

Uncertain

0.0040

D;D

Sift4G

Uncertain

0.0020

D;D

Polyphen

0.98

D;D

Vest4

0.92

MVP

0.97

MPC

0.64

ClinPred

0.69

GERP RS

5.7

Varity_R

0.83

gMVP

0.90

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over