11-65593485-C-G

Variant names:

• chr11-65593485-C-G
• rs146161072
• NM_033347.2:c.709G>C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_033347.2(KCNK7):​c.709G>C​(p.Ala237Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000291 in 1,613,664 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A237S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000026 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000029 (0 hom.)
• Consequence: KCNK7 NM_033347.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.184

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 Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNK7	NM_033347.2	c.709G>C	p.Ala237Pro	missense_variant	Exon 2 of 3	ENST00000340313.5	NP_203133.1
KCNK7	NM_005714.2	c.709G>C	p.Ala237Pro	missense_variant	Exon 2 of 2		NP_005705.1
KCNK7	NM_033348.2	c.709G>C	p.Ala237Pro	missense_variant	Exon 2 of 4		NP_203134.1
KCNK7	NM_033455.2	c.709G>C	p.Ala237Pro	missense_variant	Exon 2 of 3		NP_258416.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KCNK7	ENST00000340313.5	c.709G>C	p.Ala237Pro	missense_variant	Exon 2 of 3	1	NM_033347.2	ENSP00000344820.5

Frequencies

GnomAD3 genomes AF: 0.0000263 AC: 4 AN: 152158 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

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: 0.0000943

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000404 AC: 10 AN: 247524 Hom.: 0 AF XY: 0.0000298 AC XY: 4 AN XY: 134106

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000869

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: 0.0000633

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000294 AC: 43 AN: 1461506 Hom.: 0 Cov.: 32 AF XY: 0.0000289 AC XY: 21 AN XY: 727022

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000447

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.0000565

Gnomad4 NFE exome AF: 0.0000297

Gnomad4 OTH exome AF: 0.0000662

GnomAD4 genome AF: 0.0000263 AC: 4 AN: 152158 Hom.: 0 Cov.: 33 AF XY: 0.0000135 AC XY: 1 AN XY: 74344

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0000943

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000148 Hom.: 1

Bravo AF: 0.0000151

ExAC AF: 0.0000494 AC: 6

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jul 30, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.709G>C (p.A237P) 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 709, causing the alanine (A) at amino acid position 237 to be replaced by a proline (P). 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	Uncertain	0.36
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.21
CADD	Uncertain	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.37	.;.;.;T
Eigen	Benign	-0.13
Eigen_PC	Benign	-0.17
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Benign	0.51	.;T;T;T
M_CAP	Benign	0.041	D
MetaRNN	Uncertain	0.46	T;T;T;T
MetaSVM	Benign	-0.87	T
MutationAssessor	Uncertain	2.3	M;M;M;M
PrimateAI	Uncertain	0.53	T
PROVEAN	Uncertain	-2.9	D;D;D;N
REVEL	Benign	0.28
Sift	Benign	0.053	T;T;D;D
Sift4G	Uncertain	0.014	D;D;D;D
Polyphen		1.0	D;D;D;D
Vest4		0.33
MutPred		0.76		Loss of stability (P = 0.1278);Loss of stability (P = 0.1278);Loss of stability (P = 0.1278);Loss of stability (P = 0.1278);
MVP		0.34
MPC		0.19
ClinPred		0.71	D
GERP RS		3.3
Varity_R		0.45
gMVP		0.69

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: rs146161072; hg19: chr11-65360956;