chr2-154855301-T-C

Position:

• chr2-154855301-T-C

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_002239.4(KCNJ3):​c.1494T>C​(p.Asp498=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00406 in 1,600,582 control chromosomes in the GnomAD database, including 23 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0035 (3 hom., cov: 32)
  • Exomes 𝑓: 0.0041 (20 hom.)
• Consequence: KCNJ3 NM_002239.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.214

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 -16 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.62).
• BP6: Variant 2-154855301-T-C is Benign according to our data. Variant chr2-154855301-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 710586.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAd4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KCNJ3	NM_002239.4	c.1494T>C	p.Asp498=	synonymous_variant	3/3	ENST00000295101.3	NP_002230.1
KCNJ3	NM_001260508.2	c.*569T>C		3_prime_UTR_variant	2/2		NP_001247437.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KCNJ3	ENST00000295101.3	c.1494T>C	p.Asp498=	synonymous_variant	3/3	1	NM_002239.4	ENSP00000295101	P1
KCNJ3	ENST00000544049.2	c.*569T>C		3_prime_UTR_variant	2/2	1		ENSP00000438410
KCNJ3	ENST00000651198.1	c.957T>C	p.Asp319=	synonymous_variant	4/4			ENSP00000498639

Frequencies

GnomAD3 genomes AF: 0.00354 AC: 539 AN: 152146 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.00116

Gnomad AMI AF: 0.00658

Gnomad AMR AF: 0.00400

Gnomad ASJ AF: 0.00173

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00103

Gnomad FIN AF: 0.00160

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00575

Gnomad OTH AF: 0.00239

GnomAD3 exomes AF: 0.00317 AC: 736 AN: 232314 Hom.: 2 AF XY: 0.00295 AC XY: 373 AN XY: 126560

Gnomad AFR exome AF: 0.000929

Gnomad AMR exome AF: 0.00344

Gnomad ASJ exome AF: 0.00122

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000547

Gnomad FIN exome AF: 0.00181

Gnomad NFE exome AF: 0.00505

Gnomad OTH exome AF: 0.00379

GnomAD4 exome AF: 0.00412 AC: 5967 AN: 1448318 Hom.: 20 Cov.: 29 AF XY: 0.00393 AC XY: 2831 AN XY: 720812

Gnomad4 AFR exome AF: 0.000861

Gnomad4 AMR exome AF: 0.00362

Gnomad4 ASJ exome AF: 0.000785

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000693

Gnomad4 FIN exome AF: 0.00200

Gnomad4 NFE exome AF: 0.00488

Gnomad4 OTH exome AF: 0.00354

GnomAD4 genome AF: 0.00353 AC: 538 AN: 152264 Hom.: 3 Cov.: 32 AF XY: 0.00326 AC XY: 243 AN XY: 74430

Gnomad4 AFR AF: 0.00115

Gnomad4 AMR AF: 0.00399

Gnomad4 ASJ AF: 0.00173

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000829

Gnomad4 FIN AF: 0.00160

Gnomad4 NFE AF: 0.00575

Gnomad4 OTH AF: 0.00237

Alfa AF: 0.00478 Hom.: 0

Bravo AF: 0.00345

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2024	KCNJ3: BP4, BP7, BS2 -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Mar 29, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.62
CADD	Benign	6.1
DANN	Benign	0.62

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: rs80085601; hg19: chr2-155711813;