2-47512393-C-G

Variant names:

• chr2-47512393-C-G
• rs751759383
• ENST00000406134.5:c.2725C>G

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001406674.1(MSH2):​c.2725C>G​(p.Arg909Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,459,240 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. R909Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: MSH2 NM_001406674.1 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.32
• Publications: 0 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

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.06607732).

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.*8514G>C		3_prime_UTR	Exon 2 of 2	NP_071338.1	Q9HB15
	MSH2	NM_001406674.1		c.2725C>G	p.Arg909Gly	missense	Exon 16 of 18	NP_001393603.1
	MSH2	NM_001406631.1		c.2725C>G	p.Arg909Gly	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.2725C>G	p.Arg909Gly	missense	Exon 16 of 16	ENSP00000384199.1	E9PHA6
	KCNK12	ENST00000327876.5	TSL:1 MANE Select	c.*8514G>C		3_prime_UTR	Exon 2 of 2	ENSP00000327611.3	Q9HB15
	MSH2	ENST00000645506.1		c.2725C>G	p.Arg909Gly	missense	Exon 16 of 17	ENSP00000495455.1	A0A2R8Y6P0

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1459240 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 725726

African (AFR) AF: 0.00 AC: 0 AN: 33470

American (AMR) AF: 0.00 AC: 0 AN: 44532

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26094

East Asian (EAS) AF: 0.00 AC: 0 AN: 39672

South Asian (SAS) AF: 0.00 AC: 0 AN: 85842

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52226

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 9.00e-7 AC: 1 AN: 1111310

Other (OTH) AF: 0.00 AC: 0 AN: 60328

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.087
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.50
CADD	Benign	5.3
DANN	Benign	0.33
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.016	N
LIST_S2	Benign	0.34	T
M_CAP	Benign	0.026	D
MetaRNN	Benign	0.066	T
MetaSVM	Benign	-0.64	T
PhyloP100		-1.3
PROVEAN	Benign	-0.11	N
REVEL	Benign	0.13
Sift	Benign	0.40	T
Sift4G	Benign	0.31	T
Polyphen		0.0	B
Vest4		0.17
MutPred		0.20		Loss of helix (P = 0.0376)
MVP		0.35
ClinPred		0.019	T
GERP RS		-4.4
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: rs751759383; hg19: chr2-47739532;