rs28937875

Positions:

• chr20-10413360-C-A
• chr20-10413360-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_170784.3(MKKS):​c.155G>T​(p.Gly52Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: MKKS NM_170784.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.31

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 (HGNC:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.984

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MKKS	NM_170784.3	c.155G>T	p.Gly52Val	missense_variant	3/6	ENST00000347364.7	NP_740754.1
MKKS	NM_018848.3	c.155G>T	p.Gly52Val	missense_variant	3/6		NP_061336.1
MKKS	NR_072977.2	n.347-4557G>T		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MKKS	ENST00000347364.7	c.155G>T	p.Gly52Val	missense_variant	3/6	1	NM_170784.3	ENSP00000246062.4
MKKS	ENST00000399054.6	c.155G>T	p.Gly52Val	missense_variant	3/6	1		ENSP00000382008.2
MKKS	ENST00000651692.1	c.155G>T	p.Gly52Val	missense_variant	4/7			ENSP00000498849.1
MKKS	ENST00000652676.1	n.458+436G>T		intron_variant

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.37
BayesDel_addAF	Pathogenic	0.43	D
BayesDel_noAF	Pathogenic	0.39
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.93	D;D
Eigen	Pathogenic	0.80
Eigen_PC	Pathogenic	0.76
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.90	.;D
M_CAP	Uncertain	0.10	D
MetaRNN	Pathogenic	0.98	D;D
MetaSVM	Uncertain	0.53	D
MutationAssessor	Pathogenic	3.0	M;M
PrimateAI	Benign	0.48	T
PROVEAN	Pathogenic	-5.6	D;D
REVEL	Pathogenic	0.76
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;D
Vest4		0.91
MutPred		0.91		Loss of disorder (P = 0.2058);Loss of disorder (P = 0.2058);
MVP		0.93
MPC		0.58
ClinPred		1.0	D
GERP RS		6.1
Varity_R		0.86
gMVP		0.79

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

Other links and lift over

dbSNP: rs28937875; hg19: chr20-10394008;