11-65593824-C-G

Variant names:

• chr11-65593824-C-G
• rs751500403
• NM_033347.2:c.370G>C

Variant summary

Our verdict is Likely benign. The variant received -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. 15/22 in silico tools predict a benign outcome for this variant. 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. V124F) has been classified as Uncertain significance.

• 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
• Publications: 0 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: Likely_benign. The variant received -2 ACMG points.

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

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.370G>C	p.Val124Leu	missense	Exon 2 of 3	NP_203133.1	Q9Y2U2-1
	KCNK7	NM_005714.2		c.370G>C	p.Val124Leu	missense	Exon 2 of 2	NP_005705.1	Q9Y2U2-3
	KCNK7	NM_033348.2		c.370G>C	p.Val124Leu	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.370G>C	p.Val124Leu	missense	Exon 2 of 3	ENSP00000344820.5	Q9Y2U2-1
	KCNK7	ENST00000394216.6	TSL:1	c.370G>C	p.Val124Leu	missense	Exon 2 of 2	ENSP00000377764.2	Q9Y2U2-3
	KCNK7	ENST00000342202.8	TSL:1	c.370G>C	p.Val124Leu	missense	Exon 2 of 3	ENSP00000343923.4	Q9Y2U2-2

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

GnomAD2 exomes AF: 0.0000139 AC: 3 AN: 216146 AF XY: 0.0000169

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 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

African (AFR) AF: 0.00 AC: 0 AN: 32212

American (AMR) AF: 0.00 AC: 0 AN: 39214

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24188

East Asian (EAS) AF: 0.00 AC: 0 AN: 39162

South Asian (SAS) AF: 0.00 AC: 0 AN: 82374

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50678

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5608

European-Non Finnish (NFE) AF: 0.0000211 AC: 23 AN: 1091988

Other (OTH) AF: 0.0000171 AC: 1 AN: 58632

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

African (AFR) AF: 0.00 AC: 0 AN: 41460

American (AMR) AF: 0.00 AC: 0 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5194

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

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

European-Non Finnish (NFE) AF: 0.000103 AC: 7 AN: 68042

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000491

ExAC AF: 0.00000829 AC: 1

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	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
M_CAP	Benign	0.0061	T
MetaRNN	Benign	0.063	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.92	L
PhyloP100		-1.5
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-0.88	N
REVEL	Benign	0.038
Sift	Benign	0.23	T
Sift4G	Benign	0.27	T
Polyphen		0.0020	B
Vest4		0.13
MutPred		0.45		Loss of catalytic residue at V124 (P = 0.012)
MVP		0.21
MPC		0.022
ClinPred		0.18	T
GERP RS		3.6
PromoterAI		0.016	Neutral
Varity_R		0.076
gMVP		0.41
Mutation Taster		=90/10	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: rs751500403; hg19: chr11-65361295;