Genetic Variant NM_000890.5:c.-295_-290delCACACA (chr11-128891397-GACACAC-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.-295_-290delCACACA variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0308 in 85,488 control chromosomes in the GnomAD database, including 64 homozygotes. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.031 ( 64 hom., cov: 0)

Exomes 𝑓: 0.0029 ( 0 hom. )

Consequence

KCNJ5
NM_000890.5 5_prime_UTR

Scores

Not classified

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.140

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 nfe. GnomAd4 allele frequency = 0.0311 (2626/84444) while in subpopulation NFE AF = 0.0358 (1637/45706). AF 95% confidence interval is 0.0344. There are 64 homozygotes in GnomAd4. There are 1159 alleles in the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check.

BS2

High AC in GnomAd4 at 2626 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNJ5	NM_000890.5 link	c.-295_-290delCACACA		5_prime_UTR_variant	Exon 1 of 3	ENST00000529694.6	NP_000881.3	P48544A0A5J6E2W8
KCNJ5	NM_001354169.2 link	c.-384_-379delCACACA		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.-295_-290delCACACA	5_prime_UTR_variant	Exon 1 of 3	1	NM_000890.5	ENSP00000433295.1	P48544
KCNJ5-AS1	ENST00000730925.1 link	n.314+13028_314+13033delGTGTGT	intron_variant	Intron 2 of 2
KCNJ5-AS1	ENST00000730926.1 link	n.285+13028_285+13033delGTGTGT	intron_variant	Intron 2 of 2
KCNJ5	ENST00000338350.4 link	c.-423_-418delACACAC	upstream_gene_variant		1		ENSP00000339960.4	P48544

Frequencies

GnomAD3 genomes

AF:

0.0311

AC:

2623

AN:

84440

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0209

Gnomad AMI

AF:

0.0113

Gnomad AMR

AF:

0.0358

Gnomad ASJ

AF:

0.0424

Gnomad EAS

AF:

0.0118

Gnomad SAS

AF:

0.0316

Gnomad FIN

AF:

0.0234

Gnomad MID

AF:

0.0254

Gnomad NFE

AF:

0.0358

Gnomad OTH

AF:

0.0325

GnomAD4 exome

AF:

0.00287

AC:

AN:

1044

Hom.:

AF XY:

0.00378

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:

0.00344

AC:

AN:

872

Other (OTH)

AF:

0.00

AC:

AN:

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.016044), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.325

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0311

AC:

2626

AN:

84444

Hom.:

Cov.:

AF XY:

0.0301

AC XY:

1159

AN XY:

38536

show subpopulations

African (AFR)

AF:

0.0211

AC:

402

AN:

19072

American (AMR)

AF:

0.0357

AC:

271

AN:

7584

Ashkenazi Jewish (ASJ)

AF:

0.0424

AC:

AN:

2334

East Asian (EAS)

AF:

0.0119

AC:

AN:

2700

South Asian (SAS)

AF:

0.0318

AC:

AN:

1948

European-Finnish (FIN)

AF:

0.0234

AC:

AN:

3372

Middle Eastern (MID)

AF:

0.0263

AC:

AN:

114

European-Non Finnish (NFE)

AF:

0.0358

AC:

1637

AN:

45706

Other (OTH)

AF:

0.0323

AC:

AN:

1082

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.446

Heterozygous variant carriers

180

269

359

449

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0223

Hom.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

-0.14

Mutation Taster

=300/0

polymorphism

(source)

Splicing

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

Publications

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NM_000890.5:c.-295_-290delCACACA

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