rs74315394

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 2P and 9B. PM1BP4_StrongBP6BS2

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

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:12

Conservation

PhyloP100: 7.24

Publications

29 publications found

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 Gene-Disease associations (from GenCC):

McKusick-Kaufman syndrome
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), G2P, Orphanet
Bardet-Biedl syndrome 6
Inheritance: AR Classification: STRONG Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
Bardet-Biedl syndrome
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

MKKS links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -7 ACMG points.

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 8 uncertain in NM_170784.3

BP4

Computational evidence support a benign effect (MetaRNN=0.013411105).

BP6

Variant 20-10412791-C-A is Benign according to our data. Variant chr20-10412791-C-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 167303.

BS2

High Homozygotes in GnomAd4 at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MKKS	NM_170784.3 link	c.724G>T	p.Ala242Ser	missense_variant	Exon 3 of 6	ENST00000347364.7	NP_740754.1	Q9NPJ1B7Z3W9
MKKS	NM_018848.3 link	c.724G>T	p.Ala242Ser	missense_variant	Exon 3 of 6		NP_061336.1	Q9NPJ1B7Z3W9
MKKS	NR_072977.2 link	n.347-3988G>T		intron_variant	Intron 2 of 4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
MKKS	ENST00000347364.7 link	c.724G>T	p.Ala242Ser	missense_variant	Exon 3 of 6	1	NM_170784.3	ENSP00000246062.4	Q9NPJ1
MKKS	ENST00000399054.6 link	c.724G>T	p.Ala242Ser	missense_variant	Exon 3 of 6	1		ENSP00000382008.2	Q9NPJ1
MKKS	ENST00000651692.1 link	c.724G>T	p.Ala242Ser	missense_variant	Exon 4 of 7			ENSP00000498849.1	Q9NPJ1
MKKS	ENST00000652676.1 link	n.459-91G>T		intron_variant	Intron 3 of 6

Frequencies

GnomAD3 genomes

AF:

0.00483

AC:

735

AN:

152172

Hom.:

Cov.:

show subpopulations

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

GnomAD2 exomes

AF:

0.00521

AC:

1308

AN:

251040

AF XY:

0.00500

show subpopulations

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 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.:

Cov.:

AF XY:

0.00766

AC XY:

5568

AN XY:

727230

show subpopulations

African (AFR)

AF:

0.00140

AC:

AN:

33480

American (AMR)

AF:

0.00188

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00126

AC:

AN:

26134

East Asian (EAS)

AF:

0.00

AC:

AN:

39696

South Asian (SAS)

AF:

0.0000696

AC:

AN:

86256

European-Finnish (FIN)

AF:

0.00462

AC:

247

AN:

53418

Middle Eastern (MID)

AF:

0.000173

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00985

AC:

10958

AN:

1111994

Other (OTH)

AF:

0.00596

AC:

360

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

757

1515

2272

3030

3787

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

420

840

1260

1680

2100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00483

AC:

735

AN:

152290

Hom.:

Cov.:

AF XY:

0.00457

AC XY:

340

AN XY:

74470

show subpopulations

African (AFR)

AF:

0.00156

AC:

AN:

41570

American (AMR)

AF:

0.00236

AC:

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.000864

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5190

South Asian (SAS)

AF:

0.00

AC:

AN:

4820

European-Finnish (FIN)

AF:

0.00264

AC:

AN:

10610

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00798

AC:

543

AN:

68022

Other (OTH)

AF:

0.00426

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

110

147

184

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00762

Hom.:

Bravo

AF:

0.00476

TwinsUK

AF:

0.00782

AC:

ALSPAC

AF:

0.0101

AC:

ESP6500AA

AF:

0.00182

AC:

ESP6500EA

AF:

0.00581

AC:

ExAC

AF:

0.00556

AC:

675

EpiCase

AF:

0.00949

EpiControl

AF:

0.00688

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:12

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:6

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Mar 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

MKKS: BS1, BS2 -

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Feb 17, 2023

Mayo Clinic Laboratories, Mayo Clinic

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

BS2, PS3_moderate -

Jan 25, 2017

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:4

Apr 18, 2018

Eurofins Ntd Llc (ga)

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Mar 08, 2022

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

Jan 10, 2020

Genetic Services Laboratory, University of Chicago

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Clinical Genetics, Academic Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

McKusick-Kaufman syndrome

Uncertain:1Benign:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

Aug 22, 2023

Mendelics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Bardet-Biedl syndrome;C0948368:McKusick-Kaufman syndrome

Benign:1

Jan 27, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.28

BayesDel_addAF

Benign

-0.092

BayesDel_noAF

Uncertain

0.11

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.78

D;D

Eigen

Pathogenic

0.83

Eigen_PC

Pathogenic

0.82

FATHMM_MKL

Uncertain

0.97

LIST_S2

Benign

0.67

.;T

M_CAP

Benign

0.051

MetaRNN

Benign

0.013

T;T

MetaSVM

Uncertain

0.19

MutationAssessor

Uncertain

2.8

M;M

PhyloP100

7.2

PrimateAI

Benign

0.36

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

GERP RS

5.7

Varity_R

0.32

gMVP

0.64

Mutation Taster

=71/29

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over