2-154698959-A-G

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 3P and 4B. PM2 PP2 BP4_Strong

The NM_002239.4(KCNJ3):c.184A>G(p.Ser62Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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: not found (cov: 32)
• Consequence: KCNJ3 NM_002239.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.27

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 Likely_benign. Variant got -1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, KCNJ3
• BP4: Computational evidence support a benign effect (MetaRNN=0.040608227).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KCNJ3	NM_002239.4	c.184A>G	p.Ser62Gly	missense_variant	1/3	ENST00000295101.3
KCNJ3	NM_001260509.2	c.184A>G	p.Ser62Gly	missense_variant	1/2
KCNJ3	NM_001260510.2	c.184A>G	p.Ser62Gly	missense_variant	1/1
KCNJ3	NM_001260508.2	c.184A>G	p.Ser62Gly	missense_variant	1/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KCNJ3	ENST00000295101.3	c.184A>G	p.Ser62Gly	missense_variant	1/3	1	NM_002239.4	P1
KCNJ3	ENST00000544049.2	c.184A>G	p.Ser62Gly	missense_variant	1/2	1
KCNJ3	ENST00000651198.1	c.-42-312A>G		intron_variant

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

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 23, 2024

The c.184A>G (p.S62G) alteration is located in exon 1 (coding exon 1) of the KCNJ3 gene. This alteration results from a A to G substitution at nucleotide position 184, causing the serine (S) at amino acid position 62 to be replaced by a glycine (G). 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	0.045
BayesDel_addAF	Benign	-0.071	T
BayesDel_noAF	Benign	-0.34
Cadd	Benign	21
Dann	Benign	0.84
DEOGEN2	Uncertain	0.57	D;.
Eigen	Benign	-0.41
Eigen_PC	Benign	-0.15
FATHMM_MKL	Benign	0.70	D
LIST_S2	Benign	0.86	D;D
M_CAP	Benign	0.025	D
MetaRNN	Benign	0.041	T;T
MetaSVM	Benign	-0.40	T
MutationAssessor	Benign	-0.90	N;N
MutationTaster	Benign	0.92	D;D
PrimateAI	Uncertain	0.71	T
PROVEAN	Benign	-0.65	N;N
REVEL	Uncertain	0.34
Sift	Benign	0.82	T;T
Sift4G	Benign	0.57	T;T
Polyphen		0.0	B;.
Vest4		0.052
MutPred		0.30		Gain of methylation at R66 (P = 0.1041);Gain of methylation at R66 (P = 0.1041);
MVP		0.10
MPC		1.5
ClinPred		0.54	D
GERP RS		4.0
Varity_R		0.14
gMVP		0.83

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr2-155555471;