22-38426949-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2PP2BP4_Moderate

The NM_152868.3(KCNJ4):c.1184C>T(p.Ala395Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000031 in 1,612,356 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 31)

Exomes 𝑓: 0.0000027 ( 0 hom. )

Consequence

KCNJ4
NM_152868.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.46

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:

(HGNC:):

links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP2

Missense variant where missense usually causes diseases, KCNJ4

BP4

Computational evidence support a benign effect (MetaRNN=0.205468).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
KCNJ4	NM_152868.3 linkuse as main transcript	c.1184C>T	p.Ala395Val	missense_variant	2/2	ENST00000303592.3
LOC101927183	XR_938252.3 linkuse as main transcript	n.306+1977G>A		intron_variant, non_coding_transcript_variant
KCNJ4	NM_004981.2 linkuse as main transcript	c.1184C>T	p.Ala395Val	missense_variant	2/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KCNJ4	ENST00000303592.3 linkuse as main transcript	c.1184C>T	p.Ala395Val	missense_variant	2/2	1	NM_152868.3	P1
	ENST00000433230.1 linkuse as main transcript	n.297-128G>A		intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes

AF:

0.00000658

AC:

AN:

152088

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000274

AC:

AN:

1460268

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

726454

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

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:

0.00000270

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000658

AC:

AN:

152088

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74280

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:

0.0000147

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000756

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

Feb 06, 2023

The c.1184C>T (p.A395V) alteration is located in exon 2 (coding exon 1) of the KCNJ4 gene. This alteration results from a C to T substitution at nucleotide position 1184, causing the alanine (A) at amino acid position 395 to be replaced by a valine (V). 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

0.10

BayesDel_addAF

Benign

-0.0083

BayesDel_noAF

Benign

-0.25

Cadd

Benign

Dann

Benign

0.96

DEOGEN2

Benign

0.25

Eigen

Benign

-0.59

Eigen_PC

Benign

-0.50

FATHMM_MKL

Uncertain

0.83

LIST_S2

Benign

0.64

M_CAP

Uncertain

0.091

MetaRNN

Benign

0.21

MetaSVM

Benign

-0.65

MutationAssessor

Benign

0.0

MutationTaster

Benign

1.0

PrimateAI

Uncertain

0.61

PROVEAN

Benign

0.050

REVEL

Benign

0.17

Sift

Benign

0.17

Sift4G

Benign

0.28

Polyphen

0.059

Vest4

0.20

MVP

0.91

MPC

1.3

ClinPred

0.12

GERP RS

3.2

Varity_R

0.040

gMVP

0.45

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