rs74315394

chr20-10412791-C-A

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_170784.3(MKKS):c.724G>T(p.Ala242Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00773 in 1,614,156 control chromosomes in the GnomAD database, including 73 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0048 (4 hom., cov: 32)
  • Exomes 𝑓: 0.0080 (69 hom.)
• Consequence: MKKS NM_170784.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:12
• Conservation: PhyloP100: 7.24

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 -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.013411105).
• BS2: High Homozygotes in GnomAd at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MKKS	NM_170784.3	c.724G>T	p.Ala242Ser	missense_variant	3/6	ENST00000347364.7
MKKS	NM_018848.3	c.724G>T	p.Ala242Ser	missense_variant	3/6
MKKS	NR_072977.2	n.347-3988G>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MKKS	ENST00000347364.7	c.724G>T	p.Ala242Ser	missense_variant	3/6	1	NM_170784.3	P1
MKKS	ENST00000399054.6	c.724G>T	p.Ala242Ser	missense_variant	3/6	1		P1
MKKS	ENST00000651692.1	c.724G>T	p.Ala242Ser	missense_variant	4/7			P1
MKKS	ENST00000652676.1	n.459-91G>T		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.00483 AC: 735 AN: 152172 Hom.: 4 Cov.: 32

Gnomad AFR AF: 0.00157

Gnomad AMI AF: 0.0548

Gnomad AMR AF: 0.00236

Gnomad ASJ AF: 0.000864

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00264

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00798

Gnomad OTH AF: 0.00430

GnomAD3 exomes AF: 0.00521 AC: 1308 AN: 251040 Hom.: 10 AF XY: 0.00500 AC XY: 678 AN XY: 135714

Gnomad AFR exome AF: 0.00136

Gnomad AMR exome AF: 0.00185

Gnomad ASJ exome AF: 0.00109

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00416

Gnomad NFE exome AF: 0.00969

Gnomad OTH exome AF: 0.00344

GnomAD4 exome AF: 0.00803 AC: 11736 AN: 1461866 Hom.: 69 Cov.: 33 AF XY: 0.00766 AC XY: 5568 AN XY: 727230

Gnomad4 AFR exome AF: 0.00140

Gnomad4 AMR exome AF: 0.00188

Gnomad4 ASJ exome AF: 0.00126

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000696

Gnomad4 FIN exome AF: 0.00462

Gnomad4 NFE exome AF: 0.00985

Gnomad4 OTH exome AF: 0.00596

GnomAD4 genome AF: 0.00483 AC: 735 AN: 152290 Hom.: 4 Cov.: 32 AF XY: 0.00457 AC XY: 340 AN XY: 74470

Gnomad4 AFR AF: 0.00156

Gnomad4 AMR AF: 0.00236

Gnomad4 ASJ AF: 0.000864

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00264

Gnomad4 NFE AF: 0.00798

Gnomad4 OTH AF: 0.00426

Alfa AF: 0.00798 Hom.: 7

Bravo AF: 0.00476

TwinsUK AF: 0.00782 AC: 29

ALSPAC AF: 0.0101 AC: 39

ESP6500AA AF: 0.00182 AC: 8

ESP6500EA AF: 0.00581 AC: 50

ExAC AF: 0.00556 AC: 675

EpiCase AF: 0.00949

EpiControl AF: 0.00688

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:12

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:6

Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Feb 17, 2023	BS2, PS3_moderate -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Jan 25, 2017	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2023	MKKS: BS1, BS2 -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

not specified Benign:4

Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Mar 08, 2022	Variant summary: MKKS c.724G>T (p.Ala242Ser) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0052 in 251040 control chromosomes in the gnomAD database, including 10 homozygotes. The observed variant frequency is approximately 6.9 fold of the estimated maximal expected allele frequency for a pathogenic variant in MKKS causing Bardet-Biedl Syndrome phenotype (0.00076), strongly suggesting that the variant is benign. Although reported in the literature, to our knowledge, no penetrant association of c.724G>T in individuals affected with Bardet-Biedl Syndrome/McKusick-Kaufman syndrome and no experimental evidence demonstrating its impact on protein function have been reported. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments and a majority consensus as benign/likely benign. Based on the evidence outlined above, the variant was classified as likely benign. -
Likely benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 18, 2018	- -
Likely benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Jan 10, 2020	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

McKusick-Kaufman syndrome Uncertain:1 Benign:1

Benign, criteria provided, single submitter	clinical testing	Mendelics	Aug 22, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

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

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.28
BayesDel_addAF	Benign	-0.092	T
BayesDel_noAF	Uncertain	0.11
Cadd	Pathogenic	27
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.78	D;D
Eigen	Pathogenic	0.83
Eigen_PC	Pathogenic	0.82
FATHMM_MKL	Uncertain	0.97	D
M_CAP	Benign	0.051	D
MetaRNN	Benign	0.013	T;T
MetaSVM	Uncertain	0.19	D
MutationAssessor	Uncertain	2.8	M;M
MutationTaster	Benign	1.0	A;A
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-2.3	N;N
REVEL	Pathogenic	0.68
Sift	Uncertain	0.025	D;D
Sift4G	Uncertain	0.045	D;D
Polyphen		0.99	D;D
Vest4		0.54
MVP		0.92
MPC		0.47
ClinPred		0.033	T
GERP RS		5.7
Varity_R		0.32
gMVP		0.64

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: rs74315394; hg19: chr20-10393439; COSMIC: COSV100726345; COSMIC: COSV100726345;