20-10405290-T-C

Position:

chr20-10405290-T-C

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The ENST00000347364.7(MKKS):c.1670A>G(p.Asn557Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000967 in 1,613,336 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N557H) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000033 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00010 ( 0 hom. )

Consequence

MKKS
ENST00000347364.7 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:4

Conservation

PhyloP100: 1.51

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 Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.036670476).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
MKKS	NM_170784.3 linkuse as main transcript	c.1670A>G	p.Asn557Ser	missense_variant	6/6	ENST00000347364.7	NP_740754.1
MKKS	NM_018848.3 linkuse as main transcript	c.1670A>G	p.Asn557Ser	missense_variant	6/6		NP_061336.1
MKKS	NR_072977.2 linkuse as main transcript	n.1031A>G		non_coding_transcript_exon_variant	5/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris
MKKS	ENST00000347364.7 linkuse as main transcript	c.1670A>G	p.Asn557Ser	missense_variant	6/6	1	NM_170784.3	ENSP00000246062	P1
MKKS	ENST00000399054.6 linkuse as main transcript	c.1670A>G	p.Asn557Ser	missense_variant	6/6	1		ENSP00000382008	P1
MKKS	ENST00000651692.1 linkuse as main transcript	c.1670A>G	p.Asn557Ser	missense_variant	7/7			ENSP00000498849	P1
MKKS	ENST00000652676.1 linkuse as main transcript	n.1314A>G		non_coding_transcript_exon_variant	7/7

Frequencies

GnomAD3 genomes

AF:

0.0000328

AC:

AN:

152210

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00103

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000152

AC:

AN:

250376

Hom.:

AF XY:

0.000214

AC XY:

AN XY:

135344

show subpopulations

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:

0.00118

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000883

Gnomad OTH exome

AF:

0.000164

GnomAD4 exome

AF:

0.000103

AC:

151

AN:

1461008

Hom.:

Cov.:

AF XY:

0.000144

AC XY:

105

AN XY:

726746

show subpopulations

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:

0.00149

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000108

Gnomad4 OTH exome

AF:

0.000149

GnomAD4 genome

AF:

0.0000328

AC:

AN:

152328

Hom.:

Cov.:

AF XY:

0.0000537

AC XY:

AN XY:

74492

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00104

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000128

Hom.:

Bravo

AF:

0.0000340

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ExAC

AF:

0.000107

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

MKKS-related disorder

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 16, 2023

The MKKS c.1670A>G variant is predicted to result in the amino acid substitution p.Asn557Ser. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.12% of alleles in individuals of South Asian descent in gnomAD (http://gnomad.broadinstitute.org/variant/20-10385938-T-C). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Bardet-Biedl syndrome;C0948368:McKusick-Kaufman syndrome

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Oct 05, 2022

This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 557 of the MKKS protein (p.Asn557Ser). This variant is present in population databases (rs554429487, gnomAD 0.1%). This variant has not been reported in the literature in individuals affected with MKKS-related conditions. ClinVar contains an entry for this variant (Variation ID: 898520). 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. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

McKusick-Kaufman syndrome

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Bardet-Biedl syndrome 6

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.089

BayesDel_addAF

Benign

-0.45

BayesDel_noAF

Benign

-0.47

CADD

Benign

DANN

Benign

0.76

DEOGEN2

Benign

0.31

T;T

Eigen

Benign

-0.84

Eigen_PC

Benign

-0.63

FATHMM_MKL

Uncertain

0.78

LIST_S2

Benign

0.77

.;T

M_CAP

Benign

0.019

MetaRNN

Benign

0.037

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.77

N;N

MutationTaster

Benign

0.99

D;D

PrimateAI

Benign

0.28

PROVEAN

Benign

-0.54

N;N

REVEL

Benign

0.13

Sift

Benign

0.41

T;T

Sift4G

Benign

0.77

T;T

Polyphen

0.032

B;B

Vest4

0.17

MutPred

0.63

Loss of helix (P = 0.0558);Loss of helix (P = 0.0558);

MVP

0.74

MPC

0.11

ClinPred

0.011

GERP RS

1.2

Varity_R

0.020

gMVP

0.46

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