rs17852625

chr20-10412981-G-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 0.675

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]

ACMG classification

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	UniProt
MKKS	NM_170784.3	c.534C>T	p.Ile178=	synonymous_variant	3/6	ENST00000347364.7
MKKS	NM_018848.3	c.534C>T	p.Ile178=	synonymous_variant	3/6
MKKS	NR_072977.2	n.347-4178C>T		intron_variant, non_coding_transcript_variant

Ensembl

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

Frequencies

GnomAD3 genomes AF: 0.144 AC: 21885 AN: 151920 Hom.: 1767 Cov.: 32

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

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.: 34 AF XY: 0.127 AC XY: 92316 AN XY: 727156

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.: 32 AF XY: 0.150 AC XY: 11134 AN XY: 74322

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:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 06, 2015	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
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. -

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

Benign, criteria provided, single submitter

clinical testing

Invitae

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. -

not provided Benign:1

Likely benign, no assertion criteria provided

literature only

Department of Ophthalmology and Visual Sciences Kyoto University

-

- -

Bardet-Biedl syndrome 6 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 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

Other links and lift over

dbSNP: rs17852625; hg19: chr20-10393629; COSMIC: COSV61398029; COSMIC: COSV61398029;