NM_170784.3:c.534C>T

Variant names:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_170784.3(MKKS):c.534C>T(p.Ile178Ile) 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

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:11

Conservation

PhyloP100: 0.675

Publications

27 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 -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 VariationId is 21671.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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 rank	MANE	Protein	UniProt
MKKS	NM_170784.3 link	c.534C>T	p.Ile178Ile	synonymous_variant	Exon 3 of 6	ENST00000347364.7	NP_740754.1	Q9NPJ1B7Z3W9
MKKS	NM_018848.3 link	c.534C>T	p.Ile178Ile	synonymous_variant	Exon 3 of 6		NP_061336.1	Q9NPJ1B7Z3W9
MKKS	NR_072977.2 link	n.347-4178C>T		intron_variant	Intron 2 of 4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
MKKS	ENST00000347364.7 link	c.534C>T	p.Ile178Ile	synonymous_variant	Exon 3 of 6	1	NM_170784.3	ENSP00000246062.4	Q9NPJ1
MKKS	ENST00000399054.6 link	c.534C>T	p.Ile178Ile	synonymous_variant	Exon 3 of 6	1		ENSP00000382008.2	Q9NPJ1
MKKS	ENST00000651692.1 link	c.534C>T	p.Ile178Ile	synonymous_variant	Exon 4 of 7			ENSP00000498849.1	Q9NPJ1
MKKS	ENST00000652676.1 link	n.459-281C>T		intron_variant	Intron 3 of 6

Frequencies

GnomAD3 genomes

AF:

0.144

AC:

21885

AN:

151920

Hom.:

1767

Cov.:

show subpopulations

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

GnomAD2 exomes

AF:

0.140

AC:

35183

AN:

250930

AF XY:

0.143

show subpopulations

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 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.:

AF XY:

0.127

AC XY:

92316

AN XY:

727156

show subpopulations

African (AFR)

AF:

0.195

AC:

6521

AN:

33478

American (AMR)

AF:

0.109

AC:

4865

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.101

AC:

2652

AN:

26134

East Asian (EAS)

AF:

0.245

AC:

9709

AN:

39694

South Asian (SAS)

AF:

0.240

AC:

20694

AN:

86248

European-Finnish (FIN)

AF:

0.116

AC:

6166

AN:

53316

Middle Eastern (MID)

AF:

0.135

AC:

778

AN:

5768

European-Non Finnish (NFE)

AF:

0.110

AC:

122151

AN:

1111962

Other (OTH)

AF:

0.134

AC:

8083

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.480

Heterozygous variant carriers

10093

20187

30280

40374

50467

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:

0.144

AC:

21912

AN:

152040

Hom.:

1772

Cov.:

AF XY:

0.150

AC XY:

11134

AN XY:

74322

show subpopulations

African (AFR)

AF:

0.193

AC:

7981

AN:

41458

American (AMR)

AF:

0.151

AC:

2307

AN:

15282

Ashkenazi Jewish (ASJ)

AF:

0.105

AC:

364

AN:

3470

East Asian (EAS)

AF:

0.241

AC:

1248

AN:

5172

South Asian (SAS)

AF:

0.234

AC:

1125

AN:

4810

European-Finnish (FIN)

AF:

0.118

AC:

1249

AN:

10556

Middle Eastern (MID)

AF:

0.102

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.107

AC:

7302

AN:

67972

Other (OTH)

AF:

0.133

AC:

282

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

931

1862

2794

3725

4656

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

248

496

744

992

1240

<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:

0.129

Hom.:

858

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:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

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

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Jul 07, 2016

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

Apr 06, 2015

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

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:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Department of Ophthalmology and Visual Sciences Kyoto University

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:literature only

- -

MKKS-related disorder

Benign:1

Apr 30, 2024

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

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

Bardet-Biedl syndrome

Benign:1

Oct 13, 2009

GeneReviews

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:curation

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.67

CADD

Benign

1.1

(source)

DANN

Benign

0.40

PhyloP100

0.68

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