20-10405260-T-A

Position:

• chr20-10405260-T-A

Variant summary

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

The ENST00000347364.7(MKKS):​c.1700A>T​(p.Glu567Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: MKKS ENST00000347364.7 missense
• Clinical Significance: Uncertain significance no assertion criteria provided U:1
• Conservation: PhyloP100: 7.22

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]

ACMG classification

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	UniProt
MKKS	NM_170784.3	c.1700A>T	p.Glu567Val	missense_variant	6/6	ENST00000347364.7	NP_740754.1
MKKS	NM_018848.3	c.1700A>T	p.Glu567Val	missense_variant	6/6		NP_061336.1
MKKS	NR_072977.2	n.1061A>T		non_coding_transcript_exon_variant	5/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MKKS	ENST00000347364.7	c.1700A>T	p.Glu567Val	missense_variant	6/6	1	NM_170784.3	ENSP00000246062	P1
MKKS	ENST00000399054.6	c.1700A>T	p.Glu567Val	missense_variant	6/6	1		ENSP00000382008	P1
MKKS	ENST00000651692.1	c.1700A>T	p.Glu567Val	missense_variant	7/7			ENSP00000498849	P1
MKKS	ENST00000652676.1	n.1344A>T		non_coding_transcript_exon_variant	7/7

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: no assertion criteria provided

Submissions by phenotype

MKKS-related disorder Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 22, 2024

The MKKS c.1700A>T variant is predicted to result in the amino acid substitution p.Glu567Val. 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	0.21
BayesDel_addAF	Uncertain	0.099	D
BayesDel_noAF	Benign	-0.10
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.70	D;D
Eigen	Pathogenic	0.83
Eigen_PC	Pathogenic	0.83
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.81	.;T
M_CAP	Uncertain	0.22	D
MetaRNN	Uncertain	0.69	D;D
MetaSVM	Uncertain	0.34	D
MutationAssessor	Uncertain	2.9	M;M
MutationTaster	Benign	1.0	D;D
PrimateAI	Benign	0.47	T
PROVEAN	Uncertain	-3.3	D;D
REVEL	Pathogenic	0.70
Sift	Uncertain	0.0060	D;D
Sift4G	Uncertain	0.0040	D;D
Polyphen		1.0	D;D
Vest4		0.36
MutPred		0.60		Loss of disorder (P = 0.032);Loss of disorder (P = 0.032);
MVP		0.97
MPC		0.42
ClinPred		0.99	D
GERP RS		6.1
Varity_R		0.31
gMVP		0.45

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr20-10385908;