11-128891435-C-CAGAGAG

Position:

• chr11-128891435-C-CAGAGAG

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BS1_Supporting BS2

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. 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

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 Likely_benign. Variant got -5 ACMG points.

• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00177 (150/84690) while in subpopulation SAS AF= 0.00815 (16/1962). AF 95% confidence interval is 0.00512. There are 0 homozygotes in gnomad4. There are 71 alleles in male gnomad4 subpopulation. Median coverage is 26. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High AC in GnomAd4 at 150 AD gene.

Transcripts

RefSeq

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

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KCNJ5	ENST00000529694	c.-296_-295insGAGAGA		5_prime_UTR_variant	1/3	1	NM_000890.5	ENSP00000433295.1
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

Gnomad4 AFR exome AF: 0.00

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

Gnomad4 AFR AF: 0.000620

Gnomad4 AMR AF: 0.00213

Gnomad4 ASJ AF: 0.00281

Gnomad4 EAS AF: 0.00209

Gnomad4 SAS AF: 0.00815

Gnomad4 FIN AF: 0.000399

Gnomad4 NFE AF: 0.00194

Gnomad4 OTH AF: 0.00374

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Congenital long QT syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Familial hyperaldosteronism Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs886047994; hg19: chr11-128761330;