rs137853156

Positions:

• chr20-10412542-T-G

Variant summary

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

The NM_170784.3(MKKS):​c.973A>C​(p.Thr325Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as risk factor (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: MKKS NM_170784.3 missense
• Clinical Significance: risk factor no assertion criteria provided O:1
• Conservation: PhyloP100: 0.780

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.973A>C	p.Thr325Pro	missense_variant	3/6	ENST00000347364.7	NP_740754.1
MKKS	NM_018848.3	c.973A>C	p.Thr325Pro	missense_variant	3/6		NP_061336.1
MKKS	NR_072977.2	n.347-3739A>C		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MKKS	ENST00000347364.7	c.973A>C	p.Thr325Pro	missense_variant	3/6	1	NM_170784.3	ENSP00000246062.4
MKKS	ENST00000399054.6	c.973A>C	p.Thr325Pro	missense_variant	3/6	1		ENSP00000382008.2
MKKS	ENST00000651692.1	c.973A>C	p.Thr325Pro	missense_variant	4/7			ENSP00000498849.1
MKKS	ENST00000652676.1	n.617A>C		non_coding_transcript_exon_variant	4/7

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Significance: risk factor

Submissions summary: Other:1

Revision: no assertion criteria provided

Submissions by phenotype

Bardet-Biedl syndrome 1, modifier of Other:1

risk factor, no assertion criteria provided

literature only

OMIM

Jul 15, 2003

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_addAF	Benign	0.00099	T
BayesDel_noAF	Benign	-0.24
CADD	Benign	20
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.47	T;T
Eigen	Benign	0.0056
Eigen_PC	Benign	0.15
FATHMM_MKL	Uncertain	0.77	D
LIST_S2	Benign	0.68	.;T
M_CAP	Benign	0.032	D
MetaRNN	Uncertain	0.74	D;D
MetaSVM	Benign	-0.79	T
MutationAssessor	Benign	0.55	N;N
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-1.1	N;N
REVEL	Uncertain	0.42
Sift	Benign	0.077	T;T
Sift4G	Benign	0.30	T;T
Polyphen		0.64	P;P
Vest4		0.20
MutPred		0.72		Gain of glycosylation at T325 (P = 0.0225);Gain of glycosylation at T325 (P = 0.0225);
MVP		0.87
MPC		0.22
ClinPred		0.28	T
GERP RS		3.5
Varity_R		0.32
gMVP		0.76

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: rs137853156; hg19: chr20-10393190;