rs72888274

chr2-47512385-C-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The ENST00000406134.5(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. 11/12 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 ENST00000406134.5 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1 O:1
• Conservation: PhyloP100: -0.555

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 Benign. Variant got -14 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 id is 135565.Status of the report is criteria_provided_single_submitter, 1 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 male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 3 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KCNK12	NM_022055.2	c.*8522G>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.*8522G>A		3_prime_UTR_variant	2/2	1	NM_022055.2	P1

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

GnomAD3 exomes AF: 0.000815 AC: 195 AN: 239382 Hom.: 1 AF XY: 0.000761 AC XY: 100 AN XY: 131368

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 SAS exome AF: 0.0000335

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

Gnomad4 AFR exome AF: 0.00857

Gnomad4 AMR exome AF: 0.000943

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000396

Gnomad4 OTH exome AF: 0.000762

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

Gnomad4 AFR AF: 0.00927

Gnomad4 AMR AF: 0.000850

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000208

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000588

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.00156 Hom.: 1

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

Significance: Likely benign

Submissions summary: Benign:1 Other:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hereditary cancer-predisposing syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Color Diagnostics, LLC DBA Color Health

Feb 09, 2015

- -

not specified Other:1

not provided, no classification provided

reference population

ITMI

Sep 19, 2013

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
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;T
MetaRNN	Benign	0.0039	T;T
MetaSVM	Benign	-0.69	T
MutationTaster	Benign	1.0	N
Polyphen		0.0	.;B
Vest4		0.091
MVP		0.36
ClinPred		0.0017	T
GERP RS		-0.45

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs72888274; hg19: chr2-47739524; COSMIC: COSV99070993; COSMIC: COSV99070993;