Genetic Variant KCNJ3:c.-91_-88dupCCCC (chr2-154698683-T-TCCCC) – ACMG Classification: Likely_benign (-4 pts)

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BS2

The ENST00000544049.2(KCNJ3):c.-91_-88dupCCCC variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.00016 ( 0 hom., cov: 0)

Exomes 𝑓: 0.0025 ( 2 hom. )

Consequence

KCNJ3
ENST00000544049.2 5_prime_UTR

Scores

Not classified

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.896

Publications

3 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:

ENSG00000287900 (HGNC:):

ENSG00000287900 links:

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new If you want to explore the variant's impact on the transcript ENST00000544049.2, check out the Mutation Effect Viewer. This is especially useful for frameshift variants or if you want to visualize the effect of exon loss / intron retention.

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -4 ACMG points.

BS2

High Homozygotes in GnomAdExome4 at 2 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000544049.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
KCNJ3	NM_002239.4	MANE Select	c.-93_-92insCCCC	upstream_gene	N/A	NP_002230.1	P48549-1
KCNJ3	NM_001260509.2		c.-93_-92insCCCC	upstream_gene	N/A	NP_001247438.1	D2X9V0
KCNJ3	NM_001260510.2		c.-93_-92insCCCC	upstream_gene	N/A	NP_001247439.1	D2XBF0

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
KCNJ3	ENST00000544049.2	TSL:1	c.-91_-88dupCCCC	5_prime_UTR	Exon 1 of 2	ENSP00000438410.1	P48549-2
KCNJ3	ENST00000651198.1		c.-42-586_-42-583dupCCCC	intron	N/A	ENSP00000498639.1	A0A494C0M7
ENSG00000287900	ENST00000803267.1		n.766_769dupGGGG	non_coding_transcript_exon	Exon 1 of 4

Frequencies

GnomAD3 genomes

AF:

0.000157

AC:

AN:

114426

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000189

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000890

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000368

Gnomad SAS

AF:

0.000298

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000174

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00247

AC:

178

AN:

71940

Hom.:

Cov.:

AF XY:

0.00252

AC XY:

AN XY:

39220

show subpopulations

African (AFR)

AF:

0.00477

AC:

AN:

3144

American (AMR)

AF:

0.00279

AC:

AN:

5732

Ashkenazi Jewish (ASJ)

AF:

0.00985

AC:

AN:

812

East Asian (EAS)

AF:

0.00410

AC:

AN:

4882

South Asian (SAS)

AF:

0.00270

AC:

AN:

8162

European-Finnish (FIN)

AF:

0.000884

AC:

AN:

14702

Middle Eastern (MID)

AF:

0.000789

AC:

AN:

1268

European-Non Finnish (NFE)

AF:

0.00268

AC:

AN:

30544

Other (OTH)

AF:

0.000371

AC:

AN:

2694

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.474

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000157

AC:

AN:

114426

Hom.:

Cov.:

AF XY:

0.000164

AC XY:

AN XY:

55012

show subpopulations

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.000189

AC:

AN:

26484

American (AMR)

AF:

0.0000890

AC:

AN:

11232

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2870

East Asian (EAS)

AF:

0.000368

AC:

AN:

2716

South Asian (SAS)

AF:

0.000298

AC:

AN:

3360

European-Finnish (FIN)

AF:

0.00

AC:

AN:

7792

Middle Eastern (MID)

AF:

0.00

AC:

AN:

262

European-Non Finnish (NFE)

AF:

0.000174

AC:

AN:

57338

Other (OTH)

AF:

0.00

AC:

AN:

1574

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.272

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

0.90

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over