2-47512394-G-A

Variant names:

• chr2-47512394-G-A
• rs116117580
• ENST00000406134.5:c.2726G>A

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BS1_Supporting BS2

The ENST00000406134.5(MSH2):​c.2726G>A​(p.Arg909Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0181 in 1,611,322 control chromosomes in the GnomAD database, including 349 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/14 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as not provided (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R909W) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.012 (15 hom., cov: 32)
  • Exomes 𝑓: 0.019 (334 hom.)
• Consequence: MSH2 ENST00000406134.5 missense
• Clinical Significance: not provided no classification provided O:1
• Conservation: PhyloP100: -1.53
• Publications: 6 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: Benign. The variant received -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.003568858).
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0118 (1799/152234) while in subpopulation NFE AF = 0.0188 (1276/67986). AF 95% confidence interval is 0.0179. There are 15 homozygotes in GnomAd4. There are 788 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High Homozygotes in GnomAd4 at 15 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNK12	NM_022055.2	c.*8513C>T		3_prime_UTR_variant	Exon 2 of 2	ENST00000327876.5	NP_071338.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KCNK12	ENST00000327876.5	c.*8513C>T		3_prime_UTR_variant	Exon 2 of 2	1	NM_022055.2	ENSP00000327611.3

Frequencies

GnomAD3 genomes AF: 0.0118 AC: 1799 AN: 152116 Hom.: 15 Cov.: 32

Gnomad AFR AF: 0.00365

Gnomad AMI AF: 0.00658

Gnomad AMR AF: 0.0101

Gnomad ASJ AF: 0.0294

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00698

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.0188

Gnomad OTH AF: 0.0139

GnomAD2 exomes AF: 0.0116 AC: 2755 AN: 238202 AF XY: 0.0117

Gnomad AFR exome AF: 0.00356

Gnomad AMR exome AF: 0.00541

Gnomad ASJ exome AF: 0.0275

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00730

Gnomad NFE exome AF: 0.0189

Gnomad OTH exome AF: 0.0132

GnomAD4 exome AF: 0.0187 AC: 27336 AN: 1459088 Hom.: 334 Cov.: 30 AF XY: 0.0182 AC XY: 13196 AN XY: 725636

African (AFR) AF: 0.00269 AC: 90 AN: 33478

American (AMR) AF: 0.00616 AC: 274 AN: 44508

Ashkenazi Jewish (ASJ) AF: 0.0285 AC: 744 AN: 26094

East Asian (EAS) AF: 0.00 AC: 0 AN: 39668

South Asian (SAS) AF: 0.000909 AC: 78 AN: 85852

European-Finnish (FIN) AF: 0.00799 AC: 417 AN: 52216

Middle Eastern (MID) AF: 0.00711 AC: 41 AN: 5764

European-Non Finnish (NFE) AF: 0.0223 AC: 24827 AN: 1111182

Other (OTH) AF: 0.0143 AC: 865 AN: 60326

GnomAD4 genome AF: 0.0118 AC: 1799 AN: 152234 Hom.: 15 Cov.: 32 AF XY: 0.0106 AC XY: 788 AN XY: 74430

African (AFR) AF: 0.00364 AC: 151 AN: 41538

American (AMR) AF: 0.0101 AC: 155 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.0294 AC: 102 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5190

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4820

European-Finnish (FIN) AF: 0.00698 AC: 74 AN: 10606

Middle Eastern (MID) AF: 0.0136 AC: 4 AN: 294

European-Non Finnish (NFE) AF: 0.0188 AC: 1276 AN: 67986

Other (OTH) AF: 0.0137 AC: 29 AN: 2114

Alfa AF: 0.0160 Hom.: 14

Bravo AF: 0.0118

TwinsUK AF: 0.0210 AC: 78

ALSPAC AF: 0.0213 AC: 82

ESP6500AA AF: 0.00228 AC: 4

ESP6500EA AF: 0.0188 AC: 75

ExAC AF: 0.0112 AC: 1302

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Significance: not provided

Submissions summary: Other:1

Revision: no classification provided

Submissions by phenotype

not specified Other:1

Sep 19, 2013

ITMI

Significance: not provided

Review Status: no classification provided

Collection Method: reference population

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.54	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	0.020
DANN	Benign	0.40
Eigen	Benign	-2.1
Eigen_PC	Benign	-2.2
FATHMM_MKL	Benign	0.0012	N
LIST_S2	Benign	0.41	T;T
MetaRNN	Benign	0.0036	T;T
MetaSVM	Benign	-0.80	T
PhyloP100		-1.5
PROVEAN	Benign	0.78	.;N
REVEL	Benign	0.19
Sift	Benign	0.60	.;T
Sift4G	Benign	0.60	.;T
Polyphen		0.0	.;B
Vest4		0.024
ClinPred		0.00070	T
GERP RS		-5.2
Mutation Taster		=98/2	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs116117580; hg19: chr2-47739533; COSMIC: COSV100009874;