rs1547

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_170784.3(MKKS):c.1549C>T(p.Arg517Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.126 in 1,613,998 control chromosomes in the GnomAD database, including 14,469 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R517H) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.14 ( 1803 hom., cov: 32)

Exomes 𝑓: 0.12 ( 12666 hom. )

Consequence

MKKS
NM_170784.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: 0.0360

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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0049877167).

BP6

Variant 20-10405411-G-A is Benign according to our data. Variant chr20-10405411-G-A is described in ClinVar as [Benign]. Clinvar id is 95922.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr20-10405411-G-A is described in Lovd as [Benign]. Variant chr20-10405411-G-A is described in Lovd as [Likely_benign].

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.239 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
MKKS	NM_170784.3 linkuse as main transcript	c.1549C>T	p.Arg517Cys	missense_variant	6/6	ENST00000347364.7
MKKS	NM_018848.3 linkuse as main transcript	c.1549C>T	p.Arg517Cys	missense_variant	6/6
MKKS	NR_072977.2 linkuse as main transcript	n.910C>T		non_coding_transcript_exon_variant	5/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris
MKKS	ENST00000347364.7 linkuse as main transcript	c.1549C>T	p.Arg517Cys	missense_variant	6/6	1	NM_170784.3	P1
MKKS	ENST00000399054.6 linkuse as main transcript	c.1549C>T	p.Arg517Cys	missense_variant	6/6	1		P1
MKKS	ENST00000651692.1 linkuse as main transcript	c.1549C>T	p.Arg517Cys	missense_variant	7/7			P1
MKKS	ENST00000652676.1 linkuse as main transcript	n.1193C>T		non_coding_transcript_exon_variant	7/7

Frequencies

GnomAD3 genomes

AF:

0.145

AC:

22034

AN:

152046

Hom.:

1798

Cov.:

show subpopulations

Gnomad AFR

AF:

0.194

Gnomad AMI

AF:

0.0263

Gnomad AMR

AF:

0.151

Gnomad ASJ

AF:

0.105

Gnomad EAS

AF:

0.250

Gnomad SAS

AF:

0.234

Gnomad FIN

AF:

0.118

Gnomad MID

AF:

0.0987

Gnomad NFE

AF:

0.107

Gnomad OTH

AF:

0.136

GnomAD3 exomes

AF:

0.141

AC:

35430

AN:

251398

Hom.:

2979

AF XY:

0.144

AC XY:

19576

AN XY:

135878

show subpopulations

Gnomad AFR exome

AF:

0.193

Gnomad AMR exome

AF:

0.105

Gnomad ASJ exome

AF:

0.0999

Gnomad EAS exome

AF:

0.242

Gnomad SAS exome

AF:

0.247

Gnomad FIN exome

AF:

0.115

Gnomad NFE exome

AF:

0.108

Gnomad OTH exome

AF:

0.135

GnomAD4 exome

AF:

0.124

AC:

181988

AN:

1461832

Hom.:

12666

Cov.:

AF XY:

0.127

AC XY:

92487

AN XY:

727220

show subpopulations

Gnomad4 AFR exome

AF:

0.197

Gnomad4 AMR exome

AF:

0.109

Gnomad4 ASJ exome

AF:

0.101

Gnomad4 EAS exome

AF:

0.250

Gnomad4 SAS exome

AF:

0.240

Gnomad4 FIN exome

AF:

0.116

Gnomad4 NFE exome

AF:

0.110

Gnomad4 OTH exome

AF:

0.135

GnomAD4 genome

AF:

0.145

AC:

22063

AN:

152166

Hom.:

1803

Cov.:

AF XY:

0.151

AC XY:

11217

AN XY:

74416

show subpopulations

Gnomad4 AFR

AF:

0.195

Gnomad4 AMR

AF:

0.151

Gnomad4 ASJ

AF:

0.105

Gnomad4 EAS

AF:

0.250

Gnomad4 SAS

AF:

0.234

Gnomad4 FIN

AF:

0.118

Gnomad4 NFE

AF:

0.107

Gnomad4 OTH

AF:

0.134

Alfa

AF:

0.118

Hom.:

2910

Bravo

AF:

0.145

TwinsUK

AF:

0.115

AC:

427

ALSPAC

AF:

0.125

AC:

483

ESP6500AA

AF:

0.172

AC:

757

ESP6500EA

AF:

0.112

AC:

962

ExAC

AF:

0.144

AC:

17483

Asia WGS

AF:

0.218

AC:

756

AN:

3478

EpiCase

AF:

0.110

EpiControl

AF:

0.110

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:5

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	Eurofins Ntd Llc (ga)	Sep 10, 2013	- -
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	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

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 12, 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

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jul 17, 2019

- -

Bardet-Biedl syndrome 6

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.069

BayesDel_addAF

Benign

-0.65

BayesDel_noAF

Benign

-0.56

Cadd

Benign

5.7

Dann

Benign

0.82

DEOGEN2

Benign

0.24

T;T

Eigen

Benign

-1.3

Eigen_PC

Benign

-1.3

FATHMM_MKL

Benign

0.078

MetaRNN

Benign

0.0050

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.11

N;N

MutationTaster

Benign

1.0

P;P

PrimateAI

Benign

0.20

PROVEAN

Benign

0.64

N;N

REVEL

Benign

0.18

Sift

Benign

0.19

T;T

Sift4G

Benign

0.18

T;T

Polyphen

0.0

B;B

Vest4

0.049

MPC

0.14

ClinPred

0.00063

GERP RS

-2.8

Varity_R

0.051

gMVP

0.41

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