chr20-10413360-C-T

Position:

• chr20-10413360-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2 PP3_Strong PP5

The NM_170784.3(MKKS):​c.155G>A​(p.Gly52Asp) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,461,360 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 Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: MKKS NM_170784.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:4 U:1
• Conservation: PhyloP100: 7.31

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 Likely_pathogenic. Variant got 7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.981
• PP5: Variant 20-10413360-C-T is Pathogenic according to our data. Variant chr20-10413360-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 5311.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Pathogenic=1, Likely_pathogenic=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MKKS	NM_170784.3	c.155G>A	p.Gly52Asp	missense_variant	3/6	ENST00000347364.7	NP_740754.1
MKKS	NM_018848.3	c.155G>A	p.Gly52Asp	missense_variant	3/6		NP_061336.1
MKKS	NR_072977.2	n.347-4557G>A		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MKKS	ENST00000347364.7	c.155G>A	p.Gly52Asp	missense_variant	3/6	1	NM_170784.3	ENSP00000246062.4
MKKS	ENST00000399054.6	c.155G>A	p.Gly52Asp	missense_variant	3/6	1		ENSP00000382008.2
MKKS	ENST00000651692.1	c.155G>A	p.Gly52Asp	missense_variant	4/7			ENSP00000498849.1
MKKS	ENST00000652676.1	n.458+436G>A		intron_variant

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000119 AC: 3 AN: 251140 Hom.: 0 AF XY: 0.0000147 AC XY: 2 AN XY: 135724

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: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461360 Hom.: 0 Cov.: 34 AF XY: 0.00000275 AC XY: 2 AN XY: 726850

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000671

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000756

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:4 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Bardet-Biedl syndrome 6 Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	OMIM	Sep 01, 2000	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Feb 05, 2024	- -

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

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Jan 09, 2024

- -

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

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Mar 29, 2023

For these reasons, this variant has been classified as Pathogenic. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on MKKS function (PMID: 15731008, 18094050, 20080638, 22446187). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on MKKS protein function. ClinVar contains an entry for this variant (Variation ID: 5311). This variant is also known as 1042G>A. This missense change has been observed in individual(s) with clinical features of Bardet-Biedl syndrome (PMID: 10973238; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is present in population databases (rs28937875, gnomAD 0.006%). This sequence change replaces glycine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 52 of the MKKS protein (p.Gly52Asp). -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

Mar 28, 2022

Variant summary: MKKS c.155G>A (p.Gly52Asp) 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 1.2e-05 in 251140 control chromosomes (gnomAD). c.155G>A has been reported in the literature in a compound heterozygous individual affected with Bardet-Biedl Syndrome (Slavotinek_2000). These data do not allow any conclusion about variant significance. Experimental evidence evaluating an impact on protein function demonstrated the variant: 1) has similar expression levels and tendency to occur in the insoluble fraction as the wild-type protein (Hirayama_2008); 2) may or may not successfully localize to the centromere (Kim_2005, Hirayama_2008); 3) fails to rescue bbs morphants and is predicted to function as a dominant-negative allele in vivo (Zaghloul_2010); 4) disrupts interaction of MKKS protein with other proteins such as CEP290 (Rachel_2012) and BBS12 (Seo_2010). A ClinVar submitter (evaluation after 2014) cites the variant as pathogenic. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic until additional information (especially clinical) become available. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.45
BayesDel_addAF	Pathogenic	0.30	D
BayesDel_noAF	Pathogenic	0.37
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.50	T;T
Eigen	Uncertain	0.62
Eigen_PC	Uncertain	0.61
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.88	.;D
M_CAP	Uncertain	0.085	D
MetaRNN	Pathogenic	0.98	D;D
MetaSVM	Uncertain	0.091	D
MutationAssessor	Pathogenic	3.0	M;M
PrimateAI	Uncertain	0.56	T
PROVEAN	Benign	-1.5	N;N
REVEL	Uncertain	0.59
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;D
Vest4		0.92
MutPred		0.95		Loss of catalytic residue at Y53 (P = 0.1115);Loss of catalytic residue at Y53 (P = 0.1115);
MVP		0.91
MPC		0.58
ClinPred		0.95	D
GERP RS		6.1
Varity_R		0.48
gMVP		0.73

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

Other links and lift over

dbSNP: rs28937875; hg19: chr20-10394008;