2-154699025-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2 PP2 PP3_Moderate

The NM_002239.4(KCNJ3):c.250C>T(p.Leu84Phe) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: KCNJ3 NM_002239.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.09

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 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, KCNJ3
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.882

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KCNJ3	NM_002239.4	c.250C>T	p.Leu84Phe	missense_variant	1/3	ENST00000295101.3
KCNJ3	NM_001260509.2	c.250C>T	p.Leu84Phe	missense_variant	1/2
KCNJ3	NM_001260510.2	c.250C>T	p.Leu84Phe	missense_variant	1/1
KCNJ3	NM_001260508.2	c.250C>T	p.Leu84Phe	missense_variant	1/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KCNJ3	ENST00000295101.3	c.250C>T	p.Leu84Phe	missense_variant	1/3	1	NM_002239.4	P1
KCNJ3	ENST00000544049.2	c.250C>T	p.Leu84Phe	missense_variant	1/2	1
KCNJ3	ENST00000651198.1	c.-42-246C>T		intron_variant

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

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

Jan 24, 2024

The c.250C>T (p.L84F) alteration is located in exon 1 (coding exon 1) of the KCNJ3 gene. This alteration results from a C to T substitution at nucleotide position 250, causing the leucine (L) at amino acid position 84 to be replaced by a phenylalanine (F). 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	0.43
BayesDel_addAF	Pathogenic	0.20	D
BayesDel_noAF	Uncertain	0.060
Cadd	Uncertain	25
Dann	Uncertain	1.0
DEOGEN2	Pathogenic	0.89	D;.
Eigen	Benign	0.051
Eigen_PC	Benign	0.16
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Uncertain	0.96	D;D
M_CAP	Uncertain	0.25	D
MetaRNN	Pathogenic	0.88	D;D
MetaSVM	Uncertain	0.72	D
MutationAssessor	Benign	1.6	L;L
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.81	D
PROVEAN	Uncertain	-3.2	D;D
REVEL	Pathogenic	0.72
Sift	Benign	0.036	D;D
Sift4G	Uncertain	0.047	D;T
Polyphen		0.22	B;.
Vest4		0.80
MutPred		0.78		Gain of methylation at K79 (P = 0.0778);Gain of methylation at K79 (P = 0.0778);
MVP		0.39
MPC		2.8
ClinPred		0.98	D
GERP RS		4.3
Varity_R		0.36
gMVP		0.99

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: rs1029458808; hg19: chr2-155555537;