rs3111034

Variant names:

• chr2-154698578-G-A
• rs3111034
• ENST00000651198.1:c.-43+604G>A

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BS1 BS2

The ENST00000651198.1(KCNJ3):​c.-43+604G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.012 in 581,718 control chromosomes in the GnomAD database, including 74 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 0.012 (12 hom., cov: 31)
  • Exomes 𝑓: 0.012 (62 hom.)
• Consequence: KCNJ3 ENST00000651198.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.19

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 Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.0123 (1867/152184) while in subpopulation SAS AF= 0.0261 (126/4824). AF 95% confidence interval is 0.0224. There are 12 homozygotes in gnomad4. There are 954 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 12 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNJ3	NM_002239.4	c.-198G>A		upstream_gene_variant		ENST00000295101.3	NP_002230.1
KCNJ3	NM_001260509.2	c.-198G>A		upstream_gene_variant			NP_001247438.1
KCNJ3	NM_001260510.2	c.-198G>A		upstream_gene_variant			NP_001247439.1
KCNJ3	NM_001260508.2	c.-198G>A		upstream_gene_variant			NP_001247437.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KCNJ3	ENST00000651198.1	c.-43+604G>A		intron_variant	Intron 1 of 3			ENSP00000498639.1
KCNJ3	ENST00000295101.3	c.-198G>A		upstream_gene_variant		1	NM_002239.4	ENSP00000295101.2
KCNJ3	ENST00000544049.2	c.-198G>A		upstream_gene_variant		1		ENSP00000438410.1

Frequencies

GnomAD3 genomes AF: 0.0123 AC: 1867 AN: 152066 Hom.: 12 Cov.: 31

Gnomad AFR AF: 0.00403

Gnomad AMI AF: 0.00987

Gnomad AMR AF: 0.00962

Gnomad ASJ AF: 0.00317

Gnomad EAS AF: 0.0258

Gnomad SAS AF: 0.0259

Gnomad FIN AF: 0.00839

Gnomad MID AF: 0.00637

Gnomad NFE AF: 0.0170

Gnomad OTH AF: 0.0134

GnomAD4 exome AF: 0.0119 AC: 5128 AN: 429534 Hom.: 62 Cov.: 3 AF XY: 0.0122 AC XY: 2741 AN XY: 224316

Gnomad4 AFR exome AF: 0.00230

Gnomad4 AMR exome AF: 0.00811

Gnomad4 ASJ exome AF: 0.00307

Gnomad4 EAS exome AF: 0.0191

Gnomad4 SAS exome AF: 0.0210

Gnomad4 FIN exome AF: 0.00642

Gnomad4 NFE exome AF: 0.0119

Gnomad4 OTH exome AF: 0.00873

GnomAD4 genome AF: 0.0123 AC: 1867 AN: 152184 Hom.: 12 Cov.: 31 AF XY: 0.0128 AC XY: 954 AN XY: 74386

Gnomad4 AFR AF: 0.00402

Gnomad4 AMR AF: 0.00961

Gnomad4 ASJ AF: 0.00317

Gnomad4 EAS AF: 0.0259

Gnomad4 SAS AF: 0.0261

Gnomad4 FIN AF: 0.00839

Gnomad4 NFE AF: 0.0170

Gnomad4 OTH AF: 0.0132

Alfa AF: 0.0130 Hom.: 1

Bravo AF: 0.0119

Asia WGS AF: 0.0180 AC: 64 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	7.8
DANN	Benign	0.68

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: rs3111034; hg19: chr2-155555090;