rs17642086

Variant names:

• chr2-154854845-T-C
• rs17642086
• NM_002239.4:c.1038T>C

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP7 BA1

The NM_002239.4(KCNJ3):​c.1038T>C​(p.His346His) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.31 in 1,613,570 control chromosomes in the GnomAD database, including 82,959 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.27 (6312 hom., cov: 31)
  • Exomes 𝑓: 0.31 (76647 hom.)
• Consequence: KCNJ3 NM_002239.4 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.201
• Publications: 19 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]

ACMG classification

Our verdict: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.54).
• BP7: Synonymous conserved (PhyloP=0.201 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.346 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNJ3	NM_002239.4	c.1038T>C	p.His346His	synonymous_variant	Exon 3 of 3	ENST00000295101.3	NP_002230.1
KCNJ3	NM_001260508.2	c.*113T>C		3_prime_UTR_variant	Exon 2 of 2		NP_001247437.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KCNJ3	ENST00000295101.3	c.1038T>C	p.His346His	synonymous_variant	Exon 3 of 3	1	NM_002239.4	ENSP00000295101.2
KCNJ3	ENST00000544049.2	c.*113T>C		3_prime_UTR_variant	Exon 2 of 2	1		ENSP00000438410.1
KCNJ3	ENST00000651198.1	c.501T>C	p.His167His	synonymous_variant	Exon 4 of 4			ENSP00000498639.1
KCNJ3	ENST00000493505.1	n.381T>C		non_coding_transcript_exon_variant	Exon 3 of 3	2

Frequencies

GnomAD3 genomes AF: 0.267 AC: 40612 AN: 151874 Hom.: 6312 Cov.: 31

Gnomad AFR AF: 0.155

Gnomad AMI AF: 0.377

Gnomad AMR AF: 0.233

Gnomad ASJ AF: 0.271

Gnomad EAS AF: 0.0465

Gnomad SAS AF: 0.141

Gnomad FIN AF: 0.384

Gnomad MID AF: 0.247

Gnomad NFE AF: 0.349

Gnomad OTH AF: 0.277

GnomAD2 exomes AF: 0.263 AC: 66003 AN: 251236 AF XY: 0.265

Gnomad AFR exome AF: 0.150

Gnomad AMR exome AF: 0.189

Gnomad ASJ exome AF: 0.262

Gnomad EAS exome AF: 0.0395

Gnomad FIN exome AF: 0.367

Gnomad NFE exome AF: 0.344

Gnomad OTH exome AF: 0.298

GnomAD4 exome AF: 0.314 AC: 459528 AN: 1461576 Hom.: 76647 Cov.: 35 AF XY: 0.311 AC XY: 225905 AN XY: 727104

African (AFR) AF: 0.144 AC: 4834 AN: 33474

American (AMR) AF: 0.193 AC: 8613 AN: 44696

Ashkenazi Jewish (ASJ) AF: 0.267 AC: 6972 AN: 26132

East Asian (EAS) AF: 0.0514 AC: 2038 AN: 39678

South Asian (SAS) AF: 0.158 AC: 13600 AN: 86248

European-Finnish (FIN) AF: 0.370 AC: 19748 AN: 53414

Middle Eastern (MID) AF: 0.256 AC: 1478 AN: 5768

European-Non Finnish (NFE) AF: 0.346 AC: 384475 AN: 1111780

Other (OTH) AF: 0.294 AC: 17770 AN: 60386

GnomAD4 genome AF: 0.267 AC: 40626 AN: 151994 Hom.: 6312 Cov.: 31 AF XY: 0.265 AC XY: 19708 AN XY: 74276

African (AFR) AF: 0.155 AC: 6444 AN: 41480

American (AMR) AF: 0.232 AC: 3547 AN: 15258

Ashkenazi Jewish (ASJ) AF: 0.271 AC: 941 AN: 3472

East Asian (EAS) AF: 0.0465 AC: 240 AN: 5156

South Asian (SAS) AF: 0.140 AC: 676 AN: 4820

European-Finnish (FIN) AF: 0.384 AC: 4046 AN: 10550

Middle Eastern (MID) AF: 0.248 AC: 73 AN: 294

European-Non Finnish (NFE) AF: 0.349 AC: 23729 AN: 67938

Other (OTH) AF: 0.277 AC: 586 AN: 2114

Alfa AF: 0.318 Hom.: 31733

Bravo AF: 0.252

Asia WGS AF: 0.115 AC: 403 AN: 3478

EpiCase AF: 0.349

EpiControl AF: 0.339

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.54
CADD	Benign	5.3
DANN	Benign	0.63
PhyloP100		0.20
Mutation Taster		=96/4	polymorphism (auto)

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: rs17642086; hg19: chr2-155711357; COSMIC: COSV54536521;