chr11-65593824-C-G

Position:

• chr11-65593824-C-G

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_033347.2(KCNK7):​c.370G>C​(p.Val124Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000197 in 1,576,292 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: 𝑓 0.000046 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000017 (0 hom.)
• Consequence: KCNK7 NM_033347.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -1.50

Genes affected

KCNK7 (HGNC:6282): (potassium two pore domain channel subfamily K member 7) This gene encodes a member 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. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.06291452).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KCNK7	NM_033347.2	c.370G>C	p.Val124Leu	missense_variant	2/3	ENST00000340313.5	NP_203133.1
KCNK7	NM_005714.2	c.370G>C	p.Val124Leu	missense_variant	2/2		NP_005705.1
KCNK7	NM_033348.2	c.370G>C	p.Val124Leu	missense_variant	2/4		NP_203134.1
KCNK7	NM_033455.2	c.370G>C	p.Val124Leu	missense_variant	2/3		NP_258416.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KCNK7	ENST00000340313.5	c.370G>C	p.Val124Leu	missense_variant	2/3	1	NM_033347.2	ENSP00000344820.5
KCNK7	ENST00000394216.6	c.370G>C	p.Val124Leu	missense_variant	2/2	1		ENSP00000377764.2
KCNK7	ENST00000342202.8	c.370G>C	p.Val124Leu	missense_variant	2/3	1		ENSP00000343923.4
KCNK7	ENST00000394217.6	c.370G>C	p.Val124Leu	missense_variant	2/4	1		ENSP00000377765.2

Frequencies

GnomAD3 genomes AF: 0.0000460 AC: 7 AN: 152236 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.000103

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000139 AC: 3 AN: 216146 Hom.: 0 AF XY: 0.0000169 AC XY: 2 AN XY: 118694

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000310

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000169 AC: 24 AN: 1424056 Hom.: 0 Cov.: 32 AF XY: 0.0000142 AC XY: 10 AN XY: 704384

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

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: 0.0000211

Gnomad4 OTH exome AF: 0.0000171

GnomAD4 genome AF: 0.0000460 AC: 7 AN: 152236 Hom.: 0 Cov.: 33 AF XY: 0.0000538 AC XY: 4 AN XY: 74378

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000103

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000491

ExAC AF: 0.00000829 AC: 1

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

Sep 20, 2024

The c.370G>C (p.V124L) alteration is located in exon 2 (coding exon 2) of the KCNK7 gene. This alteration results from a G to C substitution at nucleotide position 370, causing the valine (V) at amino acid position 124 to be replaced by a leucine (L). 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	0.10
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.52
CADD	Benign	9.1
DANN	Uncertain	0.98
DEOGEN2	Benign	0.15	.;.;.;T
Eigen	Benign	-0.55
Eigen_PC	Benign	-0.42
FATHMM_MKL	Benign	0.26	N
LIST_S2	Benign	0.63	.;T;T;T
M_CAP	Benign	0.0061	T
MetaRNN	Benign	0.063	T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.92	L;L;L;L
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-0.88	N;N;N;N
REVEL	Benign	0.038
Sift	Benign	0.23	T;T;T;T
Sift4G	Benign	0.27	T;T;T;T
Polyphen		0.0020	B;B;B;B
Vest4		0.13
MutPred		0.45		Loss of catalytic residue at V124 (P = 0.012);Loss of catalytic residue at V124 (P = 0.012);Loss of catalytic residue at V124 (P = 0.012);Loss of catalytic residue at V124 (P = 0.012);
MVP		0.21
MPC		0.022
ClinPred		0.18	T
GERP RS		3.6
Varity_R		0.076
gMVP		0.41

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: rs751500403; hg19: chr11-65361295;