Genetic Variant KCNK7:p.Tyr125Cys (chr11-65593820-T-C) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

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

The NM_033347.2(KCNK7):c.374A>G(p.Tyr125Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000196 in 1,580,144 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000020 ( 0 hom. )

Consequence

KCNK7
NM_033347.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.962

Variant links:

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]

KCNK7 links:

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ACMG classification

Classification made for transcript

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 link	c.374A>G	p.Tyr125Cys	missense_variant	Exon 2 of 3	ENST00000340313.5	NP_203133.1	Q9Y2U2-1
KCNK7	NM_005714.2 link	c.374A>G	p.Tyr125Cys	missense_variant	Exon 2 of 2		NP_005705.1	Q9Y2U2-3A0A024R5F5
KCNK7	NM_033348.2 link	c.374A>G	p.Tyr125Cys	missense_variant	Exon 2 of 4		NP_203134.1	Q9Y2U2-2A0A024R5B0
KCNK7	NM_033455.2 link	c.374A>G	p.Tyr125Cys	missense_variant	Exon 2 of 3		NP_258416.1	Q9Y2U2-2A0A024R5B0Q3SYI1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
KCNK7	ENST00000340313.5 link	c.374A>G	p.Tyr125Cys	missense_variant	Exon 2 of 3	1	NM_033347.2	ENSP00000344820.5	Q9Y2U2-1
KCNK7	ENST00000394216.6 link	c.374A>G	p.Tyr125Cys	missense_variant	Exon 2 of 2	1		ENSP00000377764.2	Q9Y2U2-3
KCNK7	ENST00000342202.8 link	c.374A>G	p.Tyr125Cys	missense_variant	Exon 2 of 3	1		ENSP00000343923.4	Q9Y2U2-2
KCNK7	ENST00000394217.6 link	c.374A>G	p.Tyr125Cys	missense_variant	Exon 2 of 4	1		ENSP00000377765.2	Q9Y2U2-2

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152220

Hom.:

Cov.:

show subpopulations

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:

0.0000441

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000182

AC:

AN:

219572

Hom.:

AF XY:

0.0000249

AC XY:

AN XY:

120596

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000586

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000306

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000196

AC:

AN:

1427924

Hom.:

Cov.:

AF XY:

0.0000156

AC XY:

AN XY:

706880

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000255

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000238

Gnomad4 OTH exome

AF:

0.0000170

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152220

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74370

show subpopulations

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:

0.0000441

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000554

Hom.:

Bravo

AF:

0.0000189

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000117

AC:

ExAC

AF:

0.00000828

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jul 17, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.374A>G (p.Y125C) alteration is located in exon 2 (coding exon 2) of the KCNK7 gene. This alteration results from a A to G substitution at nucleotide position 374, causing the tyrosine (Y) at amino acid position 125 to be replaced by a cysteine (C). 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

0.25

BayesDel_addAF

Pathogenic

0.20

BayesDel_noAF

Pathogenic

0.23

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.90

.;.;.;D

Eigen

Uncertain

0.62

Eigen_PC

Uncertain

0.56

FATHMM_MKL

Uncertain

0.84

LIST_S2

Benign

0.82

.;T;T;T

M_CAP

Benign

0.053

MetaRNN

Uncertain

0.51

D;D;D;D

MetaSVM

Benign

-0.65

MutationAssessor

Pathogenic

3.8

H;H;H;H

PrimateAI

Uncertain

0.62

PROVEAN

Pathogenic

-8.1

D;D;D;D

REVEL

Uncertain

0.46

Sift

Pathogenic

0.0

D;D;D;D

Sift4G

Pathogenic

0.0010

D;D;D;D

Polyphen

1.0

D;D;D;D

Vest4

0.63

MVP

0.35

MPC

0.18

ClinPred

1.0

GERP RS

4.3

Varity_R

0.86

gMVP

0.83

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over