rs1545

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_170784.3(MKKS):c.1595G>T(p.Gly532Val) 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 1,613,980 control chromosomes in the GnomAD database, including 14,382 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.14 ( 1789 hom., cov: 32)

Exomes 𝑓: 0.12 ( 12593 hom. )

Consequence

MKKS
NM_170784.3 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11

Conservation

PhyloP100: -0.175

Publications

47 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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.006698847).

BP6

Variant 20-10405365-C-A is Benign according to our data. Variant chr20-10405365-C-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 95923.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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 rank	MANE	Protein	UniProt
MKKS	NM_170784.3 link	c.1595G>T	p.Gly532Val	missense_variant	Exon 6 of 6	ENST00000347364.7	NP_740754.1	Q9NPJ1B7Z3W9
MKKS	NM_018848.3 link	c.1595G>T	p.Gly532Val	missense_variant	Exon 6 of 6		NP_061336.1	Q9NPJ1B7Z3W9
MKKS	NR_072977.2 link	n.956G>T		non_coding_transcript_exon_variant	Exon 5 of 5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
MKKS	ENST00000347364.7 link	c.1595G>T	p.Gly532Val	missense_variant	Exon 6 of 6	1	NM_170784.3	ENSP00000246062.4	Q9NPJ1
MKKS	ENST00000399054.6 link	c.1595G>T	p.Gly532Val	missense_variant	Exon 6 of 6	1		ENSP00000382008.2	Q9NPJ1
MKKS	ENST00000651692.1 link	c.1595G>T	p.Gly532Val	missense_variant	Exon 7 of 7			ENSP00000498849.1	Q9NPJ1
MKKS	ENST00000652676.1 link	n.1239G>T		non_coding_transcript_exon_variant	Exon 7 of 7

Frequencies

GnomAD3 genomes

AF:

0.145

AC:

21996

AN:

152052

Hom.:

1784

Cov.:

show subpopulations

Gnomad AFR

AF:

0.194

Gnomad AMI

AF:

0.0264

Gnomad AMR

AF:

0.151

Gnomad ASJ

AF:

0.105

Gnomad EAS

AF:

0.241

Gnomad SAS

AF:

0.234

Gnomad FIN

AF:

0.119

Gnomad MID

AF:

0.0981

Gnomad NFE

AF:

0.107

Gnomad OTH

AF:

0.136

GnomAD2 exomes

AF:

0.140

AC:

35257

AN:

251320

AF XY:

0.144

show subpopulations

Gnomad AFR exome

AF:

0.192

Gnomad AMR exome

AF:

0.105

Gnomad ASJ exome

AF:

0.0999

Gnomad EAS exome

AF:

0.233

Gnomad FIN exome

AF:

0.115

Gnomad NFE exome

AF:

0.108

Gnomad OTH exome

AF:

0.134

GnomAD4 exome

AF:

0.124

AC:

181734

AN:

1461808

Hom.:

12593

Cov.:

AF XY:

0.127

AC XY:

92366

AN XY:

727210

show subpopulations

African (AFR)

AF:

0.197

AC:

6596

AN:

33478

American (AMR)

AF:

0.109

AC:

4870

AN:

44716

Ashkenazi Jewish (ASJ)

AF:

0.101

AC:

2652

AN:

26134

East Asian (EAS)

AF:

0.245

AC:

9713

AN:

39700

South Asian (SAS)

AF:

0.240

AC:

20705

AN:

86252

European-Finnish (FIN)

AF:

0.116

AC:

6175

AN:

53414

Middle Eastern (MID)

AF:

0.136

AC:

784

AN:

5768

European-Non Finnish (NFE)

AF:

0.110

AC:

122143

AN:

1111956

Other (OTH)

AF:

0.134

AC:

8096

AN:

60390

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.474

Heterozygous variant carriers

9501

19001

28502

38002

47503

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

4692

9384

14076

18768

23460

<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:

0.145

AC:

22025

AN:

152172

Hom.:

1789

Cov.:

AF XY:

0.150

AC XY:

11195

AN XY:

74394

show subpopulations

African (AFR)

AF:

0.195

AC:

8078

AN:

41524

American (AMR)

AF:

0.151

AC:

2302

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.105

AC:

365

AN:

3472

East Asian (EAS)

AF:

0.241

AC:

1248

AN:

5168

South Asian (SAS)

AF:

0.234

AC:

1127

AN:

4810

European-Finnish (FIN)

AF:

0.119

AC:

1256

AN:

10592

Middle Eastern (MID)

AF:

0.102

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.108

AC:

7313

AN:

68008

Other (OTH)

AF:

0.134

AC:

282

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

973

1946

2920

3893

4866

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

250

500

750

1000

1250

<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:

0.122

Hom.:

4167

Bravo

AF:

0.145

TwinsUK

AF:

0.115

AC:

427

ALSPAC

AF:

0.125

AC:

480

ESP6500AA

AF:

0.172

AC:

757

ESP6500EA

AF:

0.112

AC:

962

ExAC

AF:

0.143

AC:

17419

Asia WGS

AF:

0.214

AC:

743

AN:

3478

EpiCase

AF:

0.110

EpiControl

AF:

0.110

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:6

Dec 03, 2021

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

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Sep 10, 2013

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

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

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Jul 17, 2019

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 24400638, 20498079, 18813213) -

Bardet-Biedl syndrome;C0948368:McKusick-Kaufman syndrome

Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

McKusick-Kaufman syndrome

Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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

Jan 13, 2018

Illumina Laboratory Services, Illumina

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

0.074

BayesDel_addAF

Benign

-0.51

BayesDel_noAF

Benign

-0.36

CADD

Benign

0.22

(source)

DANN

Benign

0.88

DEOGEN2

Benign

0.39

T;T

Eigen

Benign

-0.77

Eigen_PC

Benign

-0.85

FATHMM_MKL

Benign

0.26

LIST_S2

Benign

0.50

.;T

MetaRNN

Benign

0.0067

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Uncertain

2.1

M;M

PhyloP100

-0.17

PrimateAI

Benign

0.23

PROVEAN

Benign

-1.1

N;N

REVEL

Benign

0.18

Sift

Benign

0.15

T;T

Sift4G

Benign

0.22

T;T

Polyphen

0.14

B;B

Vest4

0.058

MPC

0.18

ClinPred

0.0017

GERP RS

-1.6

Varity_R

0.035

gMVP

0.54

Mutation Taster

=100/0

polymorphism (auto)

(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