Genetic Variant KCNJ5:c.-305_-290delCACACACACACACACA (chr11-128891397-GACACACACACACACAC-G) – ACMG Classification: Benign (-8 pts)

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BS1BS2

The NM_000890.5(KCNJ5):c.-305_-290delCACACACACACACACA variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00741 in 85,692 control chromosomes in the GnomAD database, including 11 homozygotes. It is difficult to determine the true allele frequency of this variant because it is of type DEL_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.0075 ( 11 hom., cov: 0)

Exomes 𝑓: 0.00096 ( 0 hom. )

Consequence

KCNJ5
NM_000890.5 5_prime_UTR

Scores

Not classified

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.197

Publications

2 publications found

Variant links:

Genes affected

KCNJ5 (HGNC:6266): (potassium inwardly rectifying channel subfamily J member 5) This gene encodes an integral membrane protein which belongs to one of seven subfamilies of inward-rectifier potassium channel proteins called potassium channel subfamily J. The encoded protein is a subunit of the potassium channel which is homotetrameric. It is controlled by G-proteins and has a greater tendency to allow potassium to flow into a cell rather than out of a cell. Naturally occurring mutations in this gene are associated with aldosterone-producing adenomas. [provided by RefSeq, Aug 2017]

KCNJ5 links:

KCNJ5-AS1 (HGNC:28584): (KCNJ5 antisense RNA 1) Predicted to be located in extracellular region. [provided by Alliance of Genome Resources, Apr 2022]

KCNJ5-AS1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -8 ACMG points.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00749 (634/84648) while in subpopulation AFR AF = 0.0247 (471/19100). AF 95% confidence interval is 0.0228. There are 11 homozygotes in GnomAd4. There are 309 alleles in the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check.

BS2

High AC in GnomAd4 at 634 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNJ5	NM_000890.5 link	c.-305_-290delCACACACACACACACA		5_prime_UTR_variant	Exon 1 of 3	ENST00000529694.6	NP_000881.3	P48544A0A5J6E2W8
KCNJ5	NM_001354169.2 link	c.-394_-379delCACACACACACACACA		5_prime_UTR_variant	Exon 1 of 4		NP_001341098.1

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein	UniProt
KCNJ5	ENST00000529694.6 link	c.-305_-290delCACACACACACACACA	5_prime_UTR_variant	Exon 1 of 3	1	NM_000890.5	ENSP00000433295.1	P48544
KCNJ5-AS1	ENST00000730925.1 link	n.314+13018_314+13033delGTGTGTGTGTGTGTGT	intron_variant	Intron 2 of 2
KCNJ5-AS1	ENST00000730926.1 link	n.285+13018_285+13033delGTGTGTGTGTGTGTGT	intron_variant	Intron 2 of 2
KCNJ5	ENST00000338350.4 link	c.-423_-408delACACACACACACACAC	upstream_gene_variant		1		ENSP00000339960.4	P48544

Frequencies

GnomAD3 genomes

AF:

0.00747

AC:

632

AN:

84644

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0246

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00316

Gnomad ASJ

AF:

0.00513

Gnomad EAS

AF:

0.00294

Gnomad SAS

AF:

0.00254

Gnomad FIN

AF:

0.00355

Gnomad MID

AF:

0.00847

Gnomad NFE

AF:

0.00201

Gnomad OTH

AF:

0.00833

GnomAD4 exome

AF:

0.000958

AC:

AN:

1044

Hom.:

AF XY:

0.00

AC XY:

AN XY:

794

show subpopulations

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

African (AFR)

AF:

0.00

AC:

AN:

American (AMR)

AF:

0.00

AC:

AN:

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

East Asian (EAS)

AF:

0.00

AC:

AN:

South Asian (SAS)

AF:

0.00

AC:

AN:

European-Finnish (FIN)

AF:

0.00

AC:

AN:

Middle Eastern (MID)

AF:

0.00

AC:

AN:

European-Non Finnish (NFE)

AF:

0.00115

AC:

AN:

872

Other (OTH)

AF:

0.00

AC:

AN:

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.275

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.00749

AC:

634

AN:

84648

Hom.:

Cov.:

AF XY:

0.00800

AC XY:

309

AN XY:

38630

show subpopulations

African (AFR)

AF:

0.0247

AC:

471

AN:

19100

American (AMR)

AF:

0.00316

AC:

AN:

7598

Ashkenazi Jewish (ASJ)

AF:

0.00513

AC:

AN:

2338

East Asian (EAS)

AF:

0.00296

AC:

AN:

2704

South Asian (SAS)

AF:

0.00256

AC:

AN:

1954

European-Finnish (FIN)

AF:

0.00355

AC:

AN:

3382

Middle Eastern (MID)

AF:

0.00877

AC:

AN:

114

European-Non Finnish (NFE)

AF:

0.00201

AC:

AN:

45840

Other (OTH)

AF:

0.00829

AC:

AN:

1086

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.465

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

0.20

Splicing

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

Publications

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chr11-128891397-GACACACACACACACAC-G

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