rs748780

Variant names:

• chr2-47536756-T-C
• rs748780
• NM_022055.2:c.392-14948A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_022055.2(KCNK12):​c.392-14948A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.541 in 152,064 control chromosomes in the GnomAD database, including 24,066 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.54 (24066 hom., cov: 32)
• Consequence: KCNK12 NM_022055.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.30
• Publications: 13 publications found

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]

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 Gene-Disease associations (from GenCC):

• Lynch syndrome

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: G2P, ClinGen, Orphanet
• Lynch syndrome 1

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Ambry Genetics
• Muir-Torre syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Orphanet, G2P
• mismatch repair cancer syndrome 1

  Inheritance: AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
• mismatch repair cancer syndrome 2

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
• ovarian cancer

  Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
• malignant pancreatic neoplasm

  Inheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp
• prostate cancer

  Inheritance: AD Classification: MODERATE Submitted by: Ambry Genetics
• rhabdomyosarcoma

  Inheritance: AR Classification: MODERATE Submitted by: Genomics England PanelApp
• breast cancer

  Inheritance: AD Classification: NO_KNOWN Submitted by: Ambry Genetics
• hereditary breast carcinoma

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.76 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNK12	NM_022055.2	c.392-14948A>G		intron_variant	Intron 1 of 1	ENST00000327876.5	NP_071338.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KCNK12	ENST00000327876.5	c.392-14948A>G		intron_variant	Intron 1 of 1	1	NM_022055.2	ENSP00000327611.3

Frequencies

GnomAD3 genomes AF: 0.541 AC: 82151 AN: 151946 Hom.: 24038 Cov.: 32

Gnomad AFR AF: 0.767

Gnomad AMI AF: 0.548

Gnomad AMR AF: 0.434

Gnomad ASJ AF: 0.358

Gnomad EAS AF: 0.695

Gnomad SAS AF: 0.493

Gnomad FIN AF: 0.557

Gnomad MID AF: 0.427

Gnomad NFE AF: 0.427

Gnomad OTH AF: 0.497

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.541 AC: 82234 AN: 152064 Hom.: 24066 Cov.: 32 AF XY: 0.544 AC XY: 40419 AN XY: 74344

African (AFR) AF: 0.767 AC: 31816 AN: 41472

American (AMR) AF: 0.434 AC: 6627 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.358 AC: 1241 AN: 3464

East Asian (EAS) AF: 0.693 AC: 3585 AN: 5170

South Asian (SAS) AF: 0.493 AC: 2375 AN: 4818

European-Finnish (FIN) AF: 0.557 AC: 5892 AN: 10576

Middle Eastern (MID) AF: 0.429 AC: 126 AN: 294

European-Non Finnish (NFE) AF: 0.427 AC: 29024 AN: 67964

Other (OTH) AF: 0.497 AC: 1048 AN: 2110

Alfa AF: 0.454 Hom.: 74808

Bravo AF: 0.539

Asia WGS AF: 0.597 AC: 2079 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.32
DANN	Benign	0.62
PhyloP100		-1.3
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs748780; hg19: chr2-47763895;