Genetic Variant NM_002239.4:c.920-54287G>T (chr2-154800440-G-T) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_002239.4(KCNJ3):c.920-54287G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.52 in 151,870 control chromosomes in the GnomAD database, including 20,995 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 0.52 ( 20995 hom., cov: 32)

Consequence

KCNJ3
NM_002239.4 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.0720

Publications

4 publications found

Variant links:

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]

KCNJ3 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-1.02).

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.579 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNJ3	NM_002239.4 link	c.920-54287G>T		intron_variant	Intron 2 of 2	ENST00000295101.3	NP_002230.1	P48549-1
KCNJ3	NM_001260508.2 link	c.703-54287G>T		intron_variant	Intron 1 of 1		NP_001247437.1	P48549-2

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein	UniProt
KCNJ3	ENST00000295101.3 link	c.920-54287G>T	intron_variant	Intron 2 of 2	1	NM_002239.4	ENSP00000295101.2	P48549-1
KCNJ3	ENST00000544049.2 link	c.703-54287G>T	intron_variant	Intron 1 of 1	1		ENSP00000438410.1	P48549-2
KCNJ3	ENST00000651198.1 link	c.383-54287G>T	intron_variant	Intron 3 of 3			ENSP00000498639.1	A0A494C0M7
KCNJ3	ENST00000493505.1 link	n.263-54287G>T	intron_variant	Intron 2 of 2	2

Frequencies

GnomAD3 genomes

AF:

0.520

AC:

78953

AN:

151752

Hom.:

20985

Cov.:

show subpopulations

Gnomad AFR

AF:

0.429

Gnomad AMI

AF:

0.612

Gnomad AMR

AF:

0.488

Gnomad ASJ

AF:

0.535

Gnomad EAS

AF:

0.421

Gnomad SAS

AF:

0.508

Gnomad FIN

AF:

0.549

Gnomad MID

AF:

0.595

Gnomad NFE

AF:

0.584

Gnomad OTH

AF:

0.542

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome

AF:

0.520

AC:

79011

AN:

151870

Hom.:

20995

Cov.:

AF XY:

0.517

AC XY:

38327

AN XY:

74198

show subpopulations

African (AFR)

AF:

0.429

AC:

17769

AN:

41382

American (AMR)

AF:

0.488

AC:

7447

AN:

15256

Ashkenazi Jewish (ASJ)

AF:

0.535

AC:

1854

AN:

3468

East Asian (EAS)

AF:

0.421

AC:

2167

AN:

5150

South Asian (SAS)

AF:

0.510

AC:

2459

AN:

4824

European-Finnish (FIN)

AF:

0.549

AC:

5791

AN:

10542

Middle Eastern (MID)

AF:

0.595

AC:

175

AN:

294

European-Non Finnish (NFE)

AF:

0.584

AC:

39647

AN:

67930

Other (OTH)

AF:

0.542

AC:

1144

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

Heterozygous variant carriers

1924

3848

5772

7696

9620

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

706

1412

2118

2824

3530

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.470

Hom.:

2215

Bravo

AF:

0.511

Asia WGS

AF:

0.476

AC:

1653

AN:

3474

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-1.0

CADD

Benign

0.78

(source)

DANN

Benign

0.25

PhyloP100

-0.072

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over