chr20-10412981-G-A

Position:

chr20-10412981-G-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_170784.3(MKKS):c.534C>T(p.Ile178=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.126 in 1,613,754 control chromosomes in the GnomAD database, including 14,343 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.14 ( 1772 hom., cov: 32)

Exomes 𝑓: 0.12 ( 12571 hom. )

Consequence

MKKS
NM_170784.3 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:11

Conservation

PhyloP100: 0.675

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 Benign. Variant got -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.67).

BP6

Variant 20-10412981-G-A is Benign according to our data. Variant chr20-10412981-G-A is described in ClinVar as [Benign]. Clinvar id is 21671.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr20-10412981-G-A is described in Lovd as [Benign].

BP7

Synonymous conserved (PhyloP=0.675 with no splicing effect.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.23 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
MKKS	NM_170784.3 linkuse as main transcript	c.534C>T	p.Ile178=	synonymous_variant	3/6	ENST00000347364.7	NP_740754.1
MKKS	NM_018848.3 linkuse as main transcript	c.534C>T	p.Ile178=	synonymous_variant	3/6		NP_061336.1
MKKS	NR_072977.2 linkuse as main transcript	n.347-4178C>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris
MKKS	ENST00000347364.7 linkuse as main transcript	c.534C>T	p.Ile178=	synonymous_variant	3/6	1	NM_170784.3	ENSP00000246062	P1
MKKS	ENST00000399054.6 linkuse as main transcript	c.534C>T	p.Ile178=	synonymous_variant	3/6	1		ENSP00000382008	P1
MKKS	ENST00000651692.1 linkuse as main transcript	c.534C>T	p.Ile178=	synonymous_variant	4/7			ENSP00000498849	P1
MKKS	ENST00000652676.1 linkuse as main transcript	n.459-281C>T		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes

AF:

0.144

AC:

21885

AN:

151920

Hom.:

1767

Cov.:

show subpopulations

Gnomad AFR

AF:

0.192

Gnomad AMI

AF:

0.0263

Gnomad AMR

AF:

0.151

Gnomad ASJ

AF:

0.105

Gnomad EAS

AF:

0.241

Gnomad SAS

AF:

0.234

Gnomad FIN

AF:

0.118

Gnomad MID

AF:

0.0981

Gnomad NFE

AF:

0.107

Gnomad OTH

AF:

0.135

GnomAD3 exomes

AF:

0.140

AC:

35183

AN:

250930

Hom.:

2923

AF XY:

0.143

AC XY:

19463

AN XY:

135632

show subpopulations

Gnomad AFR exome

AF:

0.191

Gnomad AMR exome

AF:

0.105

Gnomad ASJ exome

AF:

0.0999

Gnomad EAS exome

AF:

0.233

Gnomad SAS exome

AF:

0.247

Gnomad FIN exome

AF:

0.115

Gnomad NFE exome

AF:

0.109

Gnomad OTH exome

AF:

0.135

GnomAD4 exome

AF:

0.124

AC:

181619

AN:

1461714

Hom.:

12571

Cov.:

AF XY:

0.127

AC XY:

92316

AN XY:

727156

show subpopulations

Gnomad4 AFR exome

AF:

0.195

Gnomad4 AMR exome

AF:

0.109

Gnomad4 ASJ exome

AF:

0.101

Gnomad4 EAS exome

AF:

0.245

Gnomad4 SAS exome

AF:

0.240

Gnomad4 FIN exome

AF:

0.116

Gnomad4 NFE exome

AF:

0.110

Gnomad4 OTH exome

AF:

0.134

GnomAD4 genome

AF:

0.144

AC:

21912

AN:

152040

Hom.:

1772

Cov.:

AF XY:

0.150

AC XY:

11134

AN XY:

74322

show subpopulations

Gnomad4 AFR

AF:

0.193

Gnomad4 AMR

AF:

0.151

Gnomad4 ASJ

AF:

0.105

Gnomad4 EAS

AF:

0.241

Gnomad4 SAS

AF:

0.234

Gnomad4 FIN

AF:

0.118

Gnomad4 NFE

AF:

0.107

Gnomad4 OTH

AF:

0.133

Alfa

AF:

0.119

Hom.:

600

Bravo

AF:

0.144

Asia WGS

AF:

0.213

AC:

741

AN:

3478

EpiCase

AF:

0.110

EpiControl

AF:

0.110

ClinVar

Significance: Benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 07, 2016	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 06, 2015	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

not provided

Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, no assertion criteria provided	literature only	Department of Ophthalmology and Visual Sciences Kyoto University	-	- -

MKKS-related disorder

Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 30, 2024

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Bardet-Biedl syndrome;C0948368:McKusick-Kaufman syndrome

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

McKusick-Kaufman syndrome

Benign:1

Benign, 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 and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Bardet-Biedl syndrome 6

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

Bardet-Biedl syndrome

Benign:1

Benign, no assertion criteria provided

curation

GeneReviews

Oct 13, 2009

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.67

CADD

Benign

1.1

DANN

Benign

0.40

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