11-128891435-C-CAGAGAG

Variant names:

• chr11-128891435-C-CAGAGAG
• rs886047994
• NM_000890.5:c.-296_-295insGAGAGA

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 0P and 0B.

The NM_000890.5(KCNJ5):​c.-296_-295insGAGAGA variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00177 in 84,690 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.0018 (0 hom., cov: 26)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: KCNJ5 NM_000890.5 5_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: -0.342
• Publications: 0 publications found

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

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNJ5	NM_000890.5	c.-296_-295insGAGAGA		5_prime_UTR_variant	Exon 1 of 3	ENST00000529694.6	NP_000881.3
KCNJ5	NM_001354169.2	c.-385_-384insGAGAGA		5_prime_UTR_variant	Exon 1 of 4		NP_001341098.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KCNJ5	ENST00000529694.6	c.-296_-295insGAGAGA		5_prime_UTR_variant	Exon 1 of 3	1	NM_000890.5	ENSP00000433295.1
KCNJ5-AS1	ENST00000730925.1	n.314+12995_314+12996insCTCTCT		intron_variant	Intron 2 of 2
KCNJ5-AS1	ENST00000730926.1	n.285+12995_285+12996insCTCTCT		intron_variant	Intron 2 of 2
KCNJ5	ENST00000338350.4	c.-386_-385insAGAGAG		upstream_gene_variant		1		ENSP00000339960.4

Frequencies

GnomAD3 genomes AF: 0.00178 AC: 151 AN: 84636 Hom.: 0 Cov.: 26

Gnomad AFR AF: 0.000622

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00213

Gnomad ASJ AF: 0.00281

Gnomad EAS AF: 0.00208

Gnomad SAS AF: 0.00862

Gnomad FIN AF: 0.000399

Gnomad MID AF: 0.0123

Gnomad NFE AF: 0.00194

Gnomad OTH AF: 0.00378

GnomAD4 exome Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0 AN: 412 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 318

African (AFR) AF: 0.00 AC: 0 AN: 2

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2

East Asian (EAS) AF: 0.00 AC: 0 AN: 8

South Asian (SAS) AF: 0.00 AC: 0 AN: 4

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 4

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 378

Other (OTH) AF: 0.00 AC: 0 AN: 12

GnomAD4 genome AF: 0.00177 AC: 150 AN: 84690 Hom.: 0 Cov.: 26 AF XY: 0.00177 AC XY: 71 AN XY: 40002

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

African (AFR) AF: 0.000620 AC: 12 AN: 19344

American (AMR) AF: 0.00213 AC: 19 AN: 8924

Ashkenazi Jewish (ASJ) AF: 0.00281 AC: 6 AN: 2138

East Asian (EAS) AF: 0.00209 AC: 5 AN: 2396

South Asian (SAS) AF: 0.00815 AC: 16 AN: 1962

European-Finnish (FIN) AF: 0.000399 AC: 2 AN: 5008

Middle Eastern (MID) AF: 0.0133 AC: 2 AN: 150

European-Non Finnish (NFE) AF: 0.00194 AC: 84 AN: 43244

Other (OTH) AF: 0.00374 AC: 4 AN: 1070

⚠️ 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.

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Congenital long QT syndrome Uncertain:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Familial hyperaldosteronism Uncertain:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.34

Splicing

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

Other links and lift over

dbSNP: rs886047994; hg19: chr11-128761330;