2-47521120-C-G

Position:

• chr2-47521120-C-G

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_022055.2(KCNK12):​c.1080G>C​(p.Glu360Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000801 in 1,123,870 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000080 (0 hom.)
• Consequence: KCNK12 NM_022055.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.0800

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]

ACMG classification

Verdict is Benign. Variant got -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.025582373).
• BS2: High AC in GnomAdExome4 at 9 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KCNK12	NM_022055.2	c.1080G>C	p.Glu360Asp	missense_variant	2/2	ENST00000327876.5	NP_071338.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KCNK12	ENST00000327876.5	c.1080G>C	p.Glu360Asp	missense_variant	2/2	1	NM_022055.2	ENSP00000327611.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000801 AC: 9 AN: 1123870 Hom.: 0 Cov.: 28 AF XY: 0.00000558 AC XY: 3 AN XY: 537408

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000109

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000335

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000635

Gnomad4 OTH exome AF: 0.0000221

GnomAD4 genome Cov.: 32

Bravo AF: 0.0000113

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 15, 2024

The c.1080G>C (p.E360D) alteration is located in exon 2 (coding exon 2) of the KCNK12 gene. This alteration results from a G to C substitution at nucleotide position 1080, causing the glutamic acid (E) at amino acid position 360 to be replaced by an aspartic acid (D). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.084
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.73
CADD	Benign	13
DANN	Benign	0.84
DEOGEN2	Benign	0.032	T
Eigen	Benign	-0.72
Eigen_PC	Benign	-0.52
FATHMM_MKL	Benign	0.41	N
LIST_S2	Benign	0.63	T
M_CAP	Benign	0.064	D
MetaRNN	Benign	0.026	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.47	N
PrimateAI	Pathogenic	0.90	D
PROVEAN	Benign	0.98	N
REVEL	Benign	0.16
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0010	B
Vest4		0.067
MutPred		0.13		Loss of solvent accessibility (P = 0.0509);
MVP		0.068
MPC		1.4
ClinPred		0.069	T
GERP RS		1.6
Varity_R		0.048
gMVP		0.61

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

Publications

LitVar

Other links and lift over

dbSNP: rs1042855113; hg19: chr2-47748259;