Variant 22-38427046-C-G details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_152868.3(KCNJ4):c.1087G>C(p.Ala363Pro) variant causes a missense change. The variant allele was found at a frequency of 0.0000199 in 1,460,276 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 0.000020 ( 0 hom. )

Consequence

KCNJ4
NM_152868.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.26

Variant links:

Genes affected

KCNJ4 (HGNC:6265): (potassium inwardly rectifying channel subfamily J member 4) Several different potassium channels are known to be involved with electrical signaling in the nervous system. One class is activated by depolarization whereas a second class is not. The latter are referred to as inwardly rectifying K+ channels, and they have a greater tendency to allow potassium to flow into the cell rather than out of it. This asymmetry in potassium ion conductance plays a key role in the excitability of muscle cells and neurons. The protein encoded by this gene is an integral membrane protein and member of the inward rectifier potassium channel family. The encoded protein has a small unitary conductance compared to other members of this protein family. Two transcript variants encoding the same protein have been found for this gene. [provided by RefSeq, Jul 2008]

KCNJ4 links:

ENSG00000228620 (HGNC:):

ENSG00000228620 links:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.15603635).

BS2

High AC in GnomAdExome4 at 29 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KCNJ4	NM_152868.3 linkuse as main transcript	c.1087G>C	p.Ala363Pro	missense_variant	2/2	ENST00000303592.3	NP_690607.1	P48050A0A024R1L8Q58F07
KCNJ4	NM_004981.2 linkuse as main transcript	c.1087G>C	p.Ala363Pro	missense_variant	2/2		NP_004972.1	P48050A0A024R1L8
LOC101927183	XR_938252.3 linkuse as main transcript	n.306+2074C>G		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KCNJ4	ENST00000303592.3 linkuse as main transcript	c.1087G>C	p.Ala363Pro	missense_variant	2/2	1	NM_152868.3	ENSP00000306497.3		P48050
ENSG00000228620	ENST00000433230.1 linkuse as main transcript	n.297-31C>G		intron_variant		2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000809

AC:

AN:

247088

Hom.:

AF XY:

0.0000149

AC XY:

AN XY:

134552

show subpopulations

Gnomad AFR exome

AF:

0.0000650

Gnomad AMR exome

AF:

0.00

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:

0.00000901

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000199

AC:

AN:

1460276

Hom.:

Cov.:

AF XY:

0.0000193

AC XY:

AN XY:

726442

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000261

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000312

Hom.:

Bravo

AF:

0.00000378

ExAC

AF:

0.00000824

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 05, 2024

The c.1087G>C (p.A363P) alteration is located in exon 2 (coding exon 1) of the KCNJ4 gene. This alteration results from a G to C substitution at nucleotide position 1087, causing the alanine (A) at amino acid position 363 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

Benign

0.083

BayesDel_addAF

Benign

-0.022

BayesDel_noAF

Benign

-0.090

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Benign

0.30

Eigen

Benign

-0.078

Eigen_PC

Benign

0.081

FATHMM_MKL

Benign

0.66

LIST_S2

Benign

0.69

M_CAP

Uncertain

0.094

MetaRNN

Benign

0.16

MetaSVM

Uncertain

-0.073

MutationAssessor

Benign

-0.34

PrimateAI

Uncertain

0.64

PROVEAN

Benign

-1.4

REVEL

Uncertain

0.35

Sift

Benign

0.12

Sift4G

Benign

0.16

Polyphen

0.32

Vest4

0.15

MutPred

0.47

Gain of glycosylation at A363 (P = 9e-04);

MVP

0.12

MPC

2.1

ClinPred

0.17

GERP RS

4.4

Varity_R

0.18

gMVP

0.66

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