chr2-47512385-C-T

Variant names:

• chr2-47512385-C-T
• rs72888274
• ENST00000406134.5:c.2717C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001406674.1(MSH2):​c.2717C>T​(p.Ala906Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000516 in 1,611,820 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/15 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0027 (3 hom., cov: 32)
  • Exomes 𝑓: 0.00029 (2 hom.)
• Consequence: MSH2 NM_001406674.1 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2 O:1
• Conservation: PhyloP100: -0.555
• Publications: 3 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0038554072).
• BP6: Variant 2-47512385-C-T is Benign according to our data. Variant chr2-47512385-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 135565.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00267 (406/152246) while in subpopulation AFR AF = 0.00927 (385/41538). AF 95% confidence interval is 0.00851. There are 3 homozygotes in GnomAd4. There are 185 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 3 AD,AR gene

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.*8522G>A		3_prime_UTR	Exon 2 of 2	NP_071338.1
	MSH2	NM_001406674.1		c.2717C>T	p.Ala906Val	missense	Exon 16 of 18	NP_001393603.1
	MSH2	NM_001406631.1		c.2717C>T	p.Ala906Val	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.2717C>T	p.Ala906Val	missense	Exon 16 of 16	ENSP00000384199.1
	KCNK12	ENST00000327876.5	TSL:1 MANE Select	c.*8522G>A		3_prime_UTR	Exon 2 of 2	ENSP00000327611.3
	MSH2	ENST00000645506.1		c.2717C>T	p.Ala906Val	missense	Exon 16 of 17	ENSP00000495455.1

Frequencies

GnomAD3 genomes AF: 0.00267 AC: 406 AN: 152128 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.00930

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000851

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00144

GnomAD2 exomes AF: 0.000815 AC: 195 AN: 239382 AF XY: 0.000761

Gnomad AFR exome AF: 0.0109

Gnomad AMR exome AF: 0.000996

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000941

Gnomad OTH exome AF: 0.000842

GnomAD4 exome AF: 0.000292 AC: 426 AN: 1459574 Hom.: 2 Cov.: 30 AF XY: 0.000260 AC XY: 189 AN XY: 725936

African (AFR) AF: 0.00857 AC: 287 AN: 33472

American (AMR) AF: 0.000943 AC: 42 AN: 44558

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26106

East Asian (EAS) AF: 0.00 AC: 0 AN: 39684

South Asian (SAS) AF: 0.00 AC: 0 AN: 85948

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52248

Middle Eastern (MID) AF: 0.00121 AC: 7 AN: 5768

European-Non Finnish (NFE) AF: 0.0000396 AC: 44 AN: 1111454

Other (OTH) AF: 0.000762 AC: 46 AN: 60336

GnomAD4 genome AF: 0.00267 AC: 406 AN: 152246 Hom.: 3 Cov.: 32 AF XY: 0.00249 AC XY: 185 AN XY: 74432

African (AFR) AF: 0.00927 AC: 385 AN: 41538

American (AMR) AF: 0.000850 AC: 13 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.000208 AC: 1 AN: 4818

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.0000588 AC: 4 AN: 68010

Other (OTH) AF: 0.00142 AC: 3 AN: 2110

Alfa AF: 0.00301 Hom.: 2

Bravo AF: 0.00331

ESP6500AA AF: 0.00970 AC: 17

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000887 AC: 103

Asia WGS AF: 0.000866 AC: 4 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Hereditary cancer-predisposing syndrome (1)
-	-	1	not provided (1)
-	-	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.079
BayesDel_addAF	Benign	-0.49	T
BayesDel_noAF	Benign	-0.46
CADD	Benign	11
DANN	Benign	0.72
Eigen	Benign	-0.98
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.0029	N
LIST_S2	Benign	0.50	T
MetaRNN	Benign	0.0039	T
MetaSVM	Benign	-0.69	T
PhyloP100		-0.56
PROVEAN	Benign	1.1	N
REVEL	Benign	0.095
Sift	Benign	0.21	T
Sift4G	Benign	0.34	T
Polyphen		0.0	B
Vest4		0.091
MVP		0.36
ClinPred		0.0017	T
GERP RS		-0.45
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: rs72888274; hg19: chr2-47739524; COSMIC: COSV99070993; COSMIC: COSV99070993;