chr2-47512412-A-T

Position:

• chr2-47512412-A-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The ENST00000406134.5(MSH2):​c.2744A>T​(p.Gln915Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 12/13 in silico tools predict a benign 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. Q915R) has been classified as Benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: MSH2 ENST00000406134.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.310

Genes affected

MSH2 (HGNC:7325): (mutS homolog 2) This locus is frequently mutated in hereditary nonpolyposis colon cancer (HNPCC). When cloned, it was discovered to be a human homolog of the E. coli mismatch repair gene mutS, consistent with the characteristic alterations in microsatellite sequences (RER+ phenotype) found in HNPCC. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Apr 2012]

KCNK12 (HGNC:6274): (potassium two pore domain channel subfamily K member 12) This gene encodes one of the members of the superfamily of potassium channel proteins containing two pore-forming P domains. The product of this gene has not been shown to be a functional channel, however, it may require other non-pore-forming proteins for activity. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.0736438).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KCNK12	NM_022055.2	c.*8495T>A		3_prime_UTR_variant	2/2	ENST00000327876.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KCNK12	ENST00000327876.5	c.*8495T>A		3_prime_UTR_variant	2/2	1	NM_022055.2	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 38

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.061	T
BayesDel_noAF	Benign	-0.33
CADD	Benign	2.0
DANN	Benign	0.66
Eigen	Benign	-1.7
Eigen_PC	Benign	-1.9
FATHMM_MKL	Benign	0.041	N
LIST_S2	Benign	0.27	T;T
M_CAP	Benign	0.074	D
MetaRNN	Benign	0.074	T;T
MetaSVM	Benign	-0.65	T
MutationTaster	Benign	1.0	P
PROVEAN	Benign	-0.15	.;N
REVEL	Benign	0.26
Sift	Pathogenic	0.0	.;D
Sift4G	Benign	0.092	.;T
Polyphen		0.0030	.;B
Vest4		0.17
MutPred		0.19		Gain of helix (P = 0.0164);Gain of helix (P = 0.0164);
MVP		0.41
ClinPred		0.065	T
GERP RS		-3.0

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs2303424; hg19: chr2-47739551;