rs142327258

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_170784.3(MKKS):c.1474G>T(p.Asp492Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000342 in 1,461,874 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D492N) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000034 ( 0 hom. )

Consequence

MKKS
NM_170784.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 3.29

Publications

5 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: Uncertain_significance. The variant received 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.908

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MKKS	NM_170784.3 link	c.1474G>T	p.Asp492Tyr	missense_variant	Exon 6 of 6	ENST00000347364.7	NP_740754.1	Q9NPJ1B7Z3W9
MKKS	NM_018848.3 link	c.1474G>T	p.Asp492Tyr	missense_variant	Exon 6 of 6		NP_061336.1	Q9NPJ1B7Z3W9
MKKS	NR_072977.2 link	n.835G>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.1474G>T	p.Asp492Tyr	missense_variant	Exon 6 of 6	1	NM_170784.3	ENSP00000246062.4	Q9NPJ1
MKKS	ENST00000399054.6 link	c.1474G>T	p.Asp492Tyr	missense_variant	Exon 6 of 6	1		ENSP00000382008.2	Q9NPJ1
MKKS	ENST00000651692.1 link	c.1474G>T	p.Asp492Tyr	missense_variant	Exon 7 of 7			ENSP00000498849.1	Q9NPJ1
MKKS	ENST00000652676.1 link	n.1118G>T		non_coding_transcript_exon_variant	Exon 7 of 7

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000796

AC:

AN:

251406

AF XY:

0.0000147

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000176

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000342

AC:

AN:

1461874

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

727234

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33478

American (AMR)

AF:

0.00

AC:

AN:

44718

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26134

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53418

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00000450

AC:

AN:

1112004

Other (OTH)

AF:

0.00

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.445

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome 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

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.095

BayesDel_addAF

Uncertain

0.15

BayesDel_noAF

Uncertain

-0.010

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.87

D;D

Eigen

Uncertain

0.62

Eigen_PC

Uncertain

0.60

FATHMM_MKL

Uncertain

0.93

LIST_S2

Benign

0.81

.;T

M_CAP

Uncertain

0.25

MetaRNN

Pathogenic

0.91

D;D

MetaSVM

Pathogenic

0.80

MutationAssessor

Uncertain

2.9

M;M

PhyloP100

3.3

PrimateAI

Benign

0.33

PROVEAN

Uncertain

-4.0

D;D

REVEL

Pathogenic

0.75

Sift

Uncertain

0.0050

D;D

Sift4G

Uncertain

0.0020

D;D

Polyphen

0.99

D;D

Vest4

0.53

MutPred

0.73

Loss of helix (P = 0.0376);Loss of helix (P = 0.0376);

MVP

0.98

MPC

0.56

ClinPred

0.96

GERP RS

5.1

Varity_R

0.46

gMVP

0.71

Mutation Taster

=66/34

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.37

Details are displayed if max score is > 0.2

DS_AG_spliceai

0.37

Position offset: -15

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over