2-154699366-C-T

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 0P and 11B. BP4_Moderate BP7 BS1 BS2

The NM_002239.4(KCNJ3):​c.591C>T​(p.Ser197Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0262 in 1,612,170 control chromosomes in the GnomAD database, including 639 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 0.019 (28 hom., cov: 32)
  • Exomes 𝑓: 0.027 (611 hom.)
• Consequence: KCNJ3 NM_002239.4 synonymous
• 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: Benign. The variant received -11 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.32).
• BP7: Synonymous conserved (PhyloP=0.335 with no splicing effect.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.0191 (2914/152226) while in subpopulation SAS AF = 0.0291 (140/4816). AF 95% confidence interval is 0.0271. There are 28 homozygotes in GnomAd4. There are 1418 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 28 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNJ3	NM_002239.4	c.591C>T	p.Ser197Ser	synonymous_variant	Exon 1 of 3	ENST00000295101.3	NP_002230.1
KCNJ3	NM_001260509.2	c.591C>T	p.Ser197Ser	synonymous_variant	Exon 1 of 2		NP_001247438.1
KCNJ3	NM_001260510.2	c.591C>T	p.Ser197Ser	synonymous_variant	Exon 1 of 1		NP_001247439.1
KCNJ3	NM_001260508.2	c.591C>T	p.Ser197Ser	synonymous_variant	Exon 1 of 2		NP_001247437.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KCNJ3	ENST00000295101.3	c.591C>T	p.Ser197Ser	synonymous_variant	Exon 1 of 3	1	NM_002239.4	ENSP00000295101.2

Frequencies

GnomAD3 genomes AF: 0.0192 AC: 2914 AN: 152108 Hom.: 28 Cov.: 32

Gnomad AFR AF: 0.00567

Gnomad AMI AF: 0.0121

Gnomad AMR AF: 0.0138

Gnomad ASJ AF: 0.00605

Gnomad EAS AF: 0.0256

Gnomad SAS AF: 0.0288

Gnomad FIN AF: 0.0195

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0282

Gnomad OTH AF: 0.0191

GnomAD2 exomes AF: 0.0219 AC: 5464 AN: 249706 AF XY: 0.0223

Gnomad AFR exome AF: 0.00450

Gnomad AMR exome AF: 0.0108

Gnomad ASJ exome AF: 0.00744

Gnomad EAS exome AF: 0.0314

Gnomad FIN exome AF: 0.0184

Gnomad NFE exome AF: 0.0265

Gnomad OTH exome AF: 0.0209

GnomAD4 exome AF: 0.0269 AC: 39299 AN: 1459944 Hom.: 611 Cov.: 33 AF XY: 0.0268 AC XY: 19431 AN XY: 726356

African (AFR) AF: 0.00385 AC: 129 AN: 33480

American (AMR) AF: 0.0118 AC: 527 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00784 AC: 205 AN: 26136

East Asian (EAS) AF: 0.0309 AC: 1226 AN: 39698

South Asian (SAS) AF: 0.0259 AC: 2234 AN: 86256

European-Finnish (FIN) AF: 0.0203 AC: 1047 AN: 51510

Middle Eastern (MID) AF: 0.0102 AC: 59 AN: 5768

European-Non Finnish (NFE) AF: 0.0291 AC: 32376 AN: 1111996

Other (OTH) AF: 0.0248 AC: 1496 AN: 60380

GnomAD4 genome AF: 0.0191 AC: 2914 AN: 152226 Hom.: 28 Cov.: 32 AF XY: 0.0191 AC XY: 1418 AN XY: 74406

African (AFR) AF: 0.00566 AC: 235 AN: 41552

American (AMR) AF: 0.0138 AC: 211 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.00605 AC: 21 AN: 3470

East Asian (EAS) AF: 0.0257 AC: 132 AN: 5140

South Asian (SAS) AF: 0.0291 AC: 140 AN: 4816

European-Finnish (FIN) AF: 0.0195 AC: 207 AN: 10620

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.0282 AC: 1915 AN: 68016

Other (OTH) AF: 0.0189 AC: 40 AN: 2114

Alfa AF: 0.0183 Hom.: 19

Bravo AF: 0.0181

Asia WGS AF: 0.0210 AC: 72 AN: 3478

EpiCase AF: 0.0253

EpiControl AF: 0.0242

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.32
CADD	Benign	12
DANN	Benign	0.90
PhyloP100		0.34
Mutation Taster		=69/31	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: rs3111033; hg19: chr2-155555878; COSMIC: COSV54533512; COSMIC: COSV54533512;