NM_002239.4:c.591C>G

Variant names:

• chr2-154699366-C-G
• rs3111033
• NM_002239.4:c.591C>G

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_002239.4(KCNJ3):​c.591C>G​(p.Ser197Arg) 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 pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: KCNJ3 NM_002239.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.335
• Publications: 9 publications found

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]

ENSG00000287900 (HGNC:):

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.992

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002239.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCNJ3	NM_002239.4	MANE Select	c.591C>G	p.Ser197Arg	missense	Exon 1 of 3	NP_002230.1
	KCNJ3	NM_001260509.2		c.591C>G	p.Ser197Arg	missense	Exon 1 of 2	NP_001247438.1
	KCNJ3	NM_001260510.2		c.591C>G	p.Ser197Arg	missense	Exon 1 of 1	NP_001247439.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCNJ3	ENST00000295101.3	TSL:1 MANE Select	c.591C>G	p.Ser197Arg	missense	Exon 1 of 3	ENSP00000295101.2
	KCNJ3	ENST00000544049.2	TSL:1	c.591C>G	p.Ser197Arg	missense	Exon 1 of 2	ENSP00000438410.1
	KCNJ3	ENST00000651198.1		c.54C>G	p.Ser18Arg	missense	Exon 2 of 4	ENSP00000498639.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 19

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.52	D
BayesDel_noAF	Pathogenic	0.51
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.97	D
Eigen	Pathogenic	0.69
Eigen_PC	Uncertain	0.58
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Pathogenic	0.61	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.7	H
PhyloP100		0.34
PrimateAI	Pathogenic	0.83	D
PROVEAN	Pathogenic	-4.8	D
REVEL	Pathogenic	0.95
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.98
MutPred		0.94		Gain of MoRF binding (P = 0.0321)
MVP		0.98
MPC		3.1
ClinPred		1.0	D
GERP RS		4.7
Varity_R		0.90
gMVP		1.0
Mutation Taster		=21/79	disease causing

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

Other links and lift over

dbSNP: rs3111033; hg19: chr2-155555878;