11-128891433-C-G

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_StrongBP6

The NM_000890.5(KCNJ5):c.-299C>G variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. There is a variant allele frequency bias in the population database for this variant (GnomAd4), which may indicate mosaicism or somatic mutations in the reference population data. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.14 ( 811 hom., cov: 16)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

KCNJ5
NM_000890.5 5_prime_UTR

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:1

Conservation

PhyloP100: -0.635

Publications

1 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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -5 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-1.21).

BP6

Variant 11-128891433-C-G is Benign according to our data. Variant chr11-128891433-C-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 878222.We mark this variant Likely_benign, oryginal submissions are: {Benign=1, Uncertain_significance=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNJ5	NM_000890.5 link	c.-299C>G		5_prime_UTR_variant	Exon 1 of 3	ENST00000529694.6	NP_000881.3	P48544A0A5J6E2W8
KCNJ5	NM_001354169.2 link	c.-388C>G		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.-299C>G	5_prime_UTR_variant	Exon 1 of 3	1	NM_000890.5	ENSP00000433295.1	P48544
KCNJ5-AS1	ENST00000730925.1 link	n.314+12998G>C	intron_variant	Intron 2 of 2
KCNJ5-AS1	ENST00000730926.1 link	n.285+12998G>C	intron_variant	Intron 2 of 2
KCNJ5	ENST00000338350.4 link	c.-388C>G	upstream_gene_variant		1		ENSP00000339960.4	P48544

Frequencies

GnomAD3 genomes

AF:

0.135

AC:

10928

AN:

80922

Hom.:

807

Cov.:

show subpopulations

Gnomad AFR

AF:

0.221

Gnomad AMI

AF:

0.247

Gnomad AMR

AF:

0.109

Gnomad ASJ

AF:

0.224

Gnomad EAS

AF:

0.123

Gnomad SAS

AF:

0.0583

Gnomad FIN

AF:

0.0454

Gnomad MID

AF:

0.0864

Gnomad NFE

AF:

0.112

Gnomad OTH

AF:

0.151

GnomAD4 exome

Data not reliable, filtered out with message: AC0;AS_VQSR

AF:

0.00

AC:

AN:

480

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

368

African (AFR)

AF:

0.00

AC:

AN:

American (AMR)

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:

0.00

AC:

AN:

422

Other (OTH)

AF:

0.00

AC:

AN:

GnomAD4 genome

AF:

0.135

AC:

10934

AN:

80966

Hom.:

811

Cov.:

AF XY:

0.128

AC XY:

4967

AN XY:

38726

show subpopulations

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

African (AFR)

AF:

0.221

AC:

4135

AN:

18714

American (AMR)

AF:

0.109

AC:

939

AN:

8592

Ashkenazi Jewish (ASJ)

AF:

0.224

AC:

418

AN:

1862

East Asian (EAS)

AF:

0.122

AC:

282

AN:

2308

South Asian (SAS)

AF:

0.0583

AC:

121

AN:

2076

European-Finnish (FIN)

AF:

0.0454

AC:

250

AN:

5510

Middle Eastern (MID)

AF:

0.0855

AC:

AN:

152

European-Non Finnish (NFE)

AF:

0.112

AC:

4521

AN:

40312

Other (OTH)

AF:

0.150

AC:

156

AN:

1040

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 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: 0.333

Heterozygous variant carriers

503

1005

1508

2010

2513

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Familial hyperaldosteronism type III

Uncertain:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

not provided

Benign:1

May 12, 2021

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-1.2

CADD

Benign

4.1

(source)

DANN

Benign

0.40

PhyloP100

-0.64

PromoterAI

0.076

Neutral

(source)

Mutation Taster

=300/0

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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11-128891433-C-G

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over