Variant 20-10405270-A-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The ENST00000347364.7(MKKS):c.1690T>A(p.Tyr564Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,216 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (no stars). Synonymous variant affecting the same amino acid position (i.e. Y564Y) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Consequence

MKKS
ENST00000347364.7 missense

Scores

Clinical Significance

Uncertain significance no assertion criteria provided U:1

Conservation

PhyloP100: 8.40

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:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
MKKS	NM_170784.3 linkuse as main transcript	c.1690T>A	p.Tyr564Asn	missense_variant	6/6	ENST00000347364.7	NP_740754.1
MKKS	NM_018848.3 linkuse as main transcript	c.1690T>A	p.Tyr564Asn	missense_variant	6/6		NP_061336.1
MKKS	NR_072977.2 linkuse as main transcript	n.1051T>A		non_coding_transcript_exon_variant	5/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris
MKKS	ENST00000347364.7 linkuse as main transcript	c.1690T>A	p.Tyr564Asn	missense_variant	6/6	1	NM_170784.3	ENSP00000246062	P1
MKKS	ENST00000399054.6 linkuse as main transcript	c.1690T>A	p.Tyr564Asn	missense_variant	6/6	1		ENSP00000382008	P1
MKKS	ENST00000651692.1 linkuse as main transcript	c.1690T>A	p.Tyr564Asn	missense_variant	7/7			ENSP00000498849	P1
MKKS	ENST00000652676.1 linkuse as main transcript	n.1334T>A		non_coding_transcript_exon_variant	7/7

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152216

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

Cov.:

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152216

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74372

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

MKKS-related disorder

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 26, 2024

The MKKS c.1690T>A variant is predicted to result in the amino acid substitution p.Tyr564Asn. To our knowledge, this variant has not been reported in the literature or in a large population database, indicating this variant is rare. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.19

BayesDel_addAF

Pathogenic

0.20

BayesDel_noAF

Uncertain

0.040

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.57

D;D

Eigen

Pathogenic

0.77

Eigen_PC

Pathogenic

0.79

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.90

.;D

M_CAP

Uncertain

0.11

MetaRNN

Uncertain

0.74

D;D

MetaSVM

Uncertain

0.14

MutationAssessor

Uncertain

2.9

M;M

MutationTaster

Benign

1.0

D;D

PrimateAI

Benign

0.47

PROVEAN

Uncertain

-2.5

D;D

REVEL

Uncertain

0.53

Sift

Benign

0.038

D;D

Sift4G

Pathogenic

0.0010

D;D

Polyphen

0.98

D;D

Vest4

0.63

MutPred

0.48

Gain of disorder (P = 0.0507);Gain of disorder (P = 0.0507);

MVP

0.95

MPC

0.37

ClinPred

0.98

GERP RS

6.1

Varity_R

0.20

gMVP

0.58

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