chr2-154709762-A-T

Position:

• chr2-154709762-A-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_002239.4(KCNJ3):​c.862A>T​(p.Met288Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: KCNJ3 NM_002239.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.43

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]

ACMG classification

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=0.21848482).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KCNJ3	NM_002239.4	c.862A>T	p.Met288Leu	missense_variant	2/3	ENST00000295101.3	NP_002230.1
KCNJ3	NM_001260509.2	c.862A>T	p.Met288Leu	missense_variant	2/2		NP_001247438.1
KCNJ3	NM_001260508.2	c.702+10285A>T		intron_variant			NP_001247437.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KCNJ3	ENST00000295101.3	c.862A>T	p.Met288Leu	missense_variant	2/3	1	NM_002239.4	ENSP00000295101.2
KCNJ3	ENST00000544049.2	c.702+10285A>T		intron_variant		1		ENSP00000438410.1
KCNJ3	ENST00000651198.1	c.325A>T	p.Met109Leu	missense_variant	3/4			ENSP00000498639.1
KCNJ3	ENST00000493505.1	n.205A>T		non_coding_transcript_exon_variant	2/3	2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 14, 2024

The c.862A>T (p.M288L) alteration is located in exon 2 (coding exon 2) of the KCNJ3 gene. This alteration results from a A to T substitution at nucleotide position 862, causing the methionine (M) at amino acid position 288 to be replaced by a leucine (L). 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	Uncertain	0.055	T
BayesDel_noAF	Benign	-0.16
CADD	Benign	18
DANN	Benign	0.81
DEOGEN2	Uncertain	0.51	D
Eigen	Benign	-0.44
Eigen_PC	Benign	-0.11
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.93	D
M_CAP	Benign	0.031	D
MetaRNN	Benign	0.22	T
MetaSVM	Benign	-0.58	T
MutationAssessor	Benign	-2.0	N
PrimateAI	Uncertain	0.75	T
PROVEAN	Benign	1.3	N
REVEL	Uncertain	0.44
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.43
MutPred		0.60		Loss of disorder (P = 0.1487);
MVP		0.65
MPC		0.79
ClinPred		0.37	T
GERP RS		5.4
Varity_R		0.27
gMVP		0.81

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

Other links and lift over

dbSNP: rs775437486; hg19: chr2-155566274;