2-47512412-A-T

Variant names:

• chr2-47512412-A-T
• rs2303424
• ENST00000406134.5:c.2744A>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001406674.1(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. 14/16 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. The gene MSH2 is included in the ClinGen Criteria Specification Registry.

• Frequency: Genomes: not found (cov: 32)
• Consequence: MSH2 NM_001406674.1 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.310
• Publications: 23 publications found

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

Specifications for MSH2 are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

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

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001406674.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCNK12	NM_022055.2	MANE Select	c.*8495T>A		3_prime_UTR	Exon 2 of 2	NP_071338.1	Q9HB15
	MSH2	NM_001406674.1		c.2744A>T	p.Gln915Leu	missense	Exon 16 of 18	NP_001393603.1
	MSH2	NM_001406631.1		c.2744A>T	p.Gln915Leu	missense	Exon 16 of 18	NP_001393560.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MSH2	ENST00000406134.5	TSL:1	c.2744A>T	p.Gln915Leu	missense	Exon 16 of 16	ENSP00000384199.1	E9PHA6
	KCNK12	ENST00000327876.5	TSL:1 MANE Select	c.*8495T>A		3_prime_UTR	Exon 2 of 2	ENSP00000327611.3	Q9HB15
	MSH2	ENST00000645506.1		c.2744A>T	p.Gln915Leu	missense	Exon 16 of 17	ENSP00000495455.1	A0A2R8Y6P0

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 38

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.091
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
M_CAP	Benign	0.074	D
MetaRNN	Benign	0.074	T
MetaSVM	Benign	-0.65	T
PhyloP100		0.31
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)
MVP		0.41
ClinPred		0.065	T
GERP RS		-3.0
Mutation Taster		=97/3	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs2303424; hg19: chr2-47739551;