11-128891437-C-G

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BA1

The NM_000890.5(KCNJ5):c.-295C>G variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. 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 0.23 (2300 hom., cov: 10)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: KCNJ5 NM_000890.5 5_prime_UTR
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:1
• Conservation: PhyloP100: -0.917

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]

ACMG classification

Verdict is Benign. Variant got -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-1.21).
• BP6: Variant 11-128891437-C-G is Benign according to our data. Variant chr11-128891437-C-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 303601.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=2, Benign=1}.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.359 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KCNJ5	NM_000890.5	c.-295C>G		5_prime_UTR_variant	1/3	ENST00000529694.6
KCNJ5	NM_001354169.2	c.-384C>G		5_prime_UTR_variant	1/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KCNJ5	ENST00000529694.6	c.-295C>G		5_prime_UTR_variant	1/3	1	NM_000890.5	P1
KCNJ5	ENST00000338350.4			upstream_gene_variant		1		P1

Frequencies

GnomAD3 genomes AF: 0.228 AC: 15807 AN: 69348 Hom.: 2293 Cov.: 10

Gnomad AFR AF: 0.367

Gnomad AMI AF: 0.278

Gnomad AMR AF: 0.186

Gnomad ASJ AF: 0.343

Gnomad EAS AF: 0.152

Gnomad SAS AF: 0.158

Gnomad FIN AF: 0.112

Gnomad MID AF: 0.164

Gnomad NFE AF: 0.193

Gnomad OTH AF: 0.233

GnomAD4 exome Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0 AN: 256 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 202

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.228 AC: 15810 AN: 69344 Hom.: 2300 Cov.: 10 AF XY: 0.220 AC XY: 7161 AN XY: 32494

Gnomad4 AFR AF: 0.368

Gnomad4 AMR AF: 0.185

Gnomad4 ASJ AF: 0.343

Gnomad4 EAS AF: 0.152

Gnomad4 SAS AF: 0.159

Gnomad4 FIN AF: 0.112

Gnomad4 NFE AF: 0.193

Gnomad4 OTH AF: 0.231

Alfa AF: 0.0574 Hom.: 83

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Familial hyperaldosteronism type III Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

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. -

Congenital long QT syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

May 12, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.2
Cadd	Benign	3.0
Dann	Benign	0.36

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

LitVar

Other links and lift over

dbSNP: rs372328307; hg19: chr11-128761332; COSMIC: COSV57965279; COSMIC: COSV57965279;