Genetic Variant KCNK12:c.*8472G>C (chr2-47512435-C-G) – ACMG Classification: Benign (-14 pts)

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_StrongBP6_ModerateBS1BS2

The NM_001406635.1(MSH2):c.2762+3C>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000578 in 1,599,998 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.0028 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00034 ( 3 hom. )

Consequence

MSH2
NM_001406635.1 splice_region, intron

Scores

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: -0.826

Variant links:

Genes affected

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]

KCNK12 links:

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]

MSH2 links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -14 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.86).

BP6

Variant 2-47512435-C-G is Benign according to our data. Variant chr2-47512435-C-G is described in ClinVar as [Benign]. Clinvar id is 926048.Status of the report is criteria_provided_single_submitter, 1 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00284 (433/152308) while in subpopulation AFR AF = 0.00982 (408/41560). AF 95% confidence interval is 0.00903. There are 0 homozygotes in GnomAd4. There are 195 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position FAILED quality control check.

BS2

High Homozygotes in GnomAdExome4 at 3 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNK12	NM_022055.2 link	c.*8472G>C		3_prime_UTR_variant	Exon 2 of 2	ENST00000327876.5	NP_071338.1	Q9HB15

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KCNK12	ENST00000327876 link	c.*8472G>C		3_prime_UTR_variant	Exon 2 of 2	1	NM_022055.2	ENSP00000327611.3		Q9HB15

Frequencies

GnomAD3 genomes

AF:

0.00284

AC:

432

AN:

152190

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00982

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000982

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00384

GnomAD2 exomes

AF:

0.000641

AC:

143

AN:

223112

AF XY:

0.000492

show subpopulations

Gnomad AFR exome

AF:

0.00913

Gnomad AMR exome

AF:

0.000351

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000908

Gnomad OTH exome

AF:

0.000179

GnomAD4 exome

AF:

0.000339

AC:

491

AN:

1447690

Hom.:

Cov.:

AF XY:

0.000295

AC XY:

212

AN XY:

718698

show subpopulations

Gnomad4 AFR exome

AF:

0.0116

AC:

384

AN:

33092

Gnomad4 AMR exome

AF:

0.000426

AC:

AN:

42270

Gnomad4 ASJ exome

AF:

0.00

AC:

AN:

25802

Gnomad4 EAS exome

AF:

0.00

AC:

AN:

39450

Gnomad4 SAS exome

AF:

0.0000718

AC:

AN:

83538

Gnomad4 FIN exome

AF:

0.00

AC:

AN:

51852

Gnomad4 NFE exome

AF:

0.0000235

AC:

AN:

1106040

Gnomad4 Remaining exome

AF:

0.000901

AC:

AN:

59916

Heterozygous variant carriers

105

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Exome Het

Exome Hom

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00284

AC:

433

AN:

152308

Hom.:

Cov.:

AF XY:

0.00262

AC XY:

195

AN XY:

74488

show subpopulations

Gnomad4 AFR

AF:

0.00982

AC:

0.00981713

AN:

0.00981713

Gnomad4 AMR

AF:

0.000981

AC:

0.00098052

AN:

0.00098052

Gnomad4 ASJ

AF:

0.00

AC:

AN:

Gnomad4 EAS

AF:

0.00

AC:

AN:

Gnomad4 SAS

AF:

0.00

AC:

AN:

Gnomad4 FIN

AF:

0.00

AC:

AN:

Gnomad4 NFE

AF:

0.0000294

AC:

0.0000293971

AN:

0.0000293971

Gnomad4 OTH

AF:

0.00380

AC:

0.00379507

AN:

0.00379507

Heterozygous variant carriers

109

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000804

Hom.:

Bravo

AF:

0.00308

Asia WGS

AF:

0.000577

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Hereditary cancer-predisposing syndrome

Benign:1

Apr 23, 2015

Color Diagnostics, LLC DBA Color Health

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.86

CADD

Benign

0.61

DANN

Benign

0.59

Mutation Taster

=100/0

polymorphism

Splicing

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over