11-65593485-C-G

Variant names:

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

Variant summary

Our verdict is Uncertain significance. The variant received 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
• Publications: 1 publications found

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

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

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

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_033347.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCNK7	NM_033347.2	MANE Select	c.709G>C	p.Ala237Pro	missense	Exon 2 of 3	NP_203133.1	Q9Y2U2-1
	KCNK7	NM_005714.2		c.709G>C	p.Ala237Pro	missense	Exon 2 of 2	NP_005705.1	Q9Y2U2-3
	KCNK7	NM_033348.2		c.709G>C	p.Ala237Pro	missense	Exon 2 of 4	NP_203134.1	Q9Y2U2-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCNK7	ENST00000340313.5	TSL:1 MANE Select	c.709G>C	p.Ala237Pro	missense	Exon 2 of 3	ENSP00000344820.5	Q9Y2U2-1
	KCNK7	ENST00000394216.6	TSL:1	c.709G>C	p.Ala237Pro	missense	Exon 2 of 2	ENSP00000377764.2	Q9Y2U2-3
	KCNK7	ENST00000342202.8	TSL:1	c.709G>C	p.Ala237Pro	missense	Exon 2 of 3	ENSP00000343923.4	Q9Y2U2-2

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

GnomAD2 exomes AF: 0.0000404 AC: 10 AN: 247524 AF XY: 0.0000298

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 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

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.0000447 AC: 2 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86256

European-Finnish (FIN) AF: 0.0000565 AC: 3 AN: 53054

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.0000297 AC: 33 AN: 1112004

Other (OTH) AF: 0.0000662 AC: 4 AN: 60386

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

African (AFR) AF: 0.0000241 AC: 1 AN: 41442

American (AMR) AF: 0.00 AC: 0 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.0000943 AC: 1 AN: 10610

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68022

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.0000148 Hom.: 1

Bravo AF: 0.0000151

ExAC AF: 0.0000494 AC: 6

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

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
M_CAP	Benign	0.041	D
MetaRNN	Uncertain	0.46	T
MetaSVM	Benign	-0.87	T
MutationAssessor	Uncertain	2.3	M
PhyloP100		0.18
PrimateAI	Uncertain	0.53	T
PROVEAN	Uncertain	-2.9	D
REVEL	Benign	0.28
Sift	Benign	0.053	T
Sift4G	Uncertain	0.014	D
Polyphen		1.0	D
Vest4		0.33
MutPred		0.76		Loss of stability (P = 0.1278)
MVP		0.34
MPC		0.19
ClinPred		0.71	D
GERP RS		3.3
PromoterAI		0.017	Neutral
Varity_R		0.45
gMVP		0.69
Mutation Taster		=81/19	polymorphism

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: rs146161072; hg19: chr11-65360956;