Genetic Variant KCNK2:p.Ile419Thr (chr1-215235120-T-C) – ACMG Classification: Likely_benign (-6 pts)

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_001017425.3(KCNK2):c.1256T>C(p.Ile419Thr) variant causes a missense change. The variant allele was found at a frequency of 0.0000159 in 1,446,212 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.000016 ( 0 hom. )

Consequence

KCNK2
NM_001017425.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.89

Publications

0 publications found

Variant links:

Genes affected

KCNK2 (HGNC:6277): (potassium two pore domain channel subfamily K member 2) This gene encodes one of the members of the two-pore-domain background potassium channel protein family. This type of potassium channel is formed by two homodimers that create a channel that leaks potassium out of the cell to control resting membrane potential. The channel can be opened, however, by certain anesthetics, membrane stretching, intracellular acidosis, and heat. Three transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

KCNK2 links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.16424772).

BS2

High AC in GnomAdExome4 at 23 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNK2	NM_001017425.3 link	c.1256T>C	p.Ile419Thr	missense_variant	Exon 7 of 7	ENST00000444842.7	NP_001017425.2	O95069-1Q6ZW95

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KCNK2	ENST00000444842.7 link	c.1256T>C	p.Ile419Thr	missense_variant	Exon 7 of 7	1	NM_001017425.3	ENSP00000394033.2		O95069-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000401

AC:

AN:

249324

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000886

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000159

AC:

AN:

1446212

Hom.:

Cov.:

AF XY:

0.0000112

AC XY:

AN XY:

715604

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33220

American (AMR)

AF:

0.00

AC:

AN:

44496

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25994

East Asian (EAS)

AF:

0.0000510

AC:

AN:

39212

South Asian (SAS)

AF:

0.0000116

AC:

AN:

86064

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52868

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5722

European-Non Finnish (NFE)

AF:

0.0000182

AC:

AN:

1098968

Other (OTH)

AF:

0.00

AC:

AN:

59668

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.482

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Aug 07, 2024

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.1256T>C (p.I419T) alteration is located in exon 7 (coding exon 7) of the KCNK2 gene. This alteration results from a T to C substitution at nucleotide position 1256, causing the isoleucine (I) at amino acid position 419 to be replaced by a threonine (T). 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

0.22

BayesDel_addAF

Uncertain

0.049

BayesDel_noAF

Benign

-0.17

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.18

.;.;T

Eigen

Benign

0.15

Eigen_PC

Uncertain

0.31

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Uncertain

0.94

D;D;D

M_CAP

Benign

0.018

MetaRNN

Benign

0.16

T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.6

.;.;L

PhyloP100

5.9

PrimateAI

Uncertain

0.76

PROVEAN

Benign

-0.69

N;N;N

REVEL

Benign

0.23

Sift

Pathogenic

0.0

D;D;D

Sift4G

Uncertain

0.0050

D;.;D

Polyphen

0.56

P;P;B

Vest4

0.36

MutPred

0.42

.;.;Loss of sheet (P = 0.0315);

MVP

0.51

MPC

1.0

ClinPred

0.80

GERP RS

5.6

Varity_R

0.29

gMVP

0.78

Mutation Taster

=56/44

polymorphism

(source)

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

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1-215235120-T-C

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over