2-154854757-C-T

Variant names:

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_002239.4(KCNJ3):c.950C>T(p.Thr317Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000762 in 1,613,136 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: 𝑓 0.000085 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000075 ( 0 hom. )

Consequence

KCNJ3
NM_002239.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.91

Variant links:

Genes affected

KCNJ3 (HGNC:6264): (potassium inwardly rectifying channel subfamily J member 3) Potassium channels are present in most mammalian cells, where they participate in a wide range of physiologic responses. The protein encoded by this gene is an integral membrane protein and inward-rectifier type potassium channel. The encoded protein, which has a greater tendency to allow potassium to flow into a cell rather than out of a cell, is controlled by G-proteins and plays an important role in regulating heartbeat. It associates with three other G-protein-activated potassium channels to form a heteromultimeric pore-forming complex that also couples to neurotransmitter receptors in the brain and whereby channel activation can inhibit action potential firing by hyperpolarizing the plasma membrane. These multimeric G-protein-gated inwardly-rectifying potassium (GIRK) channels may play a role in the pathophysiology of epilepsy, addiction, Down's syndrome, ataxia, and Parkinson's disease. Alternative splicing results in multiple transcript variants encoding distinct proteins. [provided by RefSeq, May 2012]

KCNJ3 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.11668983).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNJ3	NM_002239.4 link	c.950C>T	p.Thr317Ile	missense_variant	Exon 3 of 3	ENST00000295101.3	NP_002230.1	P48549-1
KCNJ3	NM_001260508.2 link	c.*25C>T		3_prime_UTR_variant	Exon 2 of 2		NP_001247437.1	P48549-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
KCNJ3	ENST00000295101.3 link	c.950C>T	p.Thr317Ile	missense_variant	Exon 3 of 3	1	NM_002239.4	ENSP00000295101.2	P48549-1
KCNJ3	ENST00000544049.2 link	c.*25C>T		3_prime_UTR_variant	Exon 2 of 2	1		ENSP00000438410.1	P48549-2
KCNJ3	ENST00000651198.1 link	c.413C>T	p.Thr138Ile	missense_variant	Exon 4 of 4			ENSP00000498639.1	A0A494C0M7
KCNJ3	ENST00000493505.1 link	n.293C>T		non_coding_transcript_exon_variant	Exon 3 of 3	2

Frequencies

GnomAD3 genomes

AF:

0.0000855

AC:

AN:

152096

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00288

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

GnomAD3 exomes

AF:

0.000168

AC:

AN:

250660

Hom.:

AF XY:

0.000155

AC XY:

AN XY:

135462

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00319

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000618

Gnomad OTH exome

AF:

0.000492

GnomAD4 exome

AF:

0.0000753

AC:

110

AN:

1461040

Hom.:

Cov.:

AF XY:

0.0000784

AC XY:

AN XY:

726734

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00291

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000207

Gnomad4 OTH exome

AF:

0.000182

GnomAD4 genome

AF:

0.0000855

AC:

AN:

152096

Hom.:

Cov.:

AF XY:

0.000108

AC XY:

AN XY:

74278

show subpopulations

Gnomad4 AFR

AF:

0.0000483

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00288

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

Alfa

AF:

0.000428

Hom.:

Bravo

AF:

0.0000831

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.000157

AC:

EpiCase

AF:

0.0000546

EpiControl

AF:

0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Oct 21, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.950C>T (p.T317I) alteration is located in exon 3 (coding exon 3) of the KCNJ3 gene. This alteration results from a C to T substitution at nucleotide position 950, causing the threonine (T) at amino acid position 317 to be replaced by an isoleucine (I). 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

Uncertain

0.47

BayesDel_addAF

Pathogenic

0.31

BayesDel_noAF

Pathogenic

0.34

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.52

Eigen

Benign

0.11

Eigen_PC

Uncertain

0.31

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.93

M_CAP

Uncertain

0.14

MetaRNN

Benign

0.12

MetaSVM

Uncertain

-0.018

MutationAssessor

Benign

1.4

PrimateAI

Pathogenic

0.94

PROVEAN

Benign

0.40

REVEL

Uncertain

0.58

Sift

Benign

0.23

Sift4G

Benign

0.20

Polyphen

0.37

Vest4

0.71

MVP

0.84

MPC

2.0

ClinPred

0.14

GERP RS

5.7

Varity_R

0.24

gMVP

0.82

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