rs780934792

Variant names:

• chr11-128916661-A-G
• rs780934792
• NM_000890.5:c.1190A>G

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 0P and 11B. BP4_Moderate BP6 BS1 BS2

The NM_000890.5(KCNJ5):​c.1190A>G​(p.Glu397Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000136 in 1,612,598 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/23 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.000026 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000012 (0 hom.)
• Consequence: KCNJ5 NM_000890.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:1
• Conservation: PhyloP100: 2.27

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

Our verdict: Benign. The variant received -11 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.13483113).
• BP6: Variant 11-128916661-A-G is Benign according to our data. Variant chr11-128916661-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 457004.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=2, Likely_benign=1}.
• BS1: Variant frequency is greater than expected in population amr. GnomAdExome4 allele frequency = 0.0000123 (18/1460450) while in subpopulation AMR AF = 0.000383 (17/44374). AF 95% confidence interval is 0.000243. There are 0 homozygotes in GnomAdExome4. There are 10 alleles in the male GnomAdExome4 subpopulation. Median coverage is 32. This position FAILED quality control check.
• BS2: High AC in GnomAdExome4 at 18 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNJ5	NM_000890.5	c.1190A>G	p.Glu397Gly	missense_variant	Exon 3 of 3	ENST00000529694.6	NP_000881.3
KCNJ5	NM_001354169.2	c.1190A>G	p.Glu397Gly	missense_variant	Exon 4 of 4		NP_001341098.1
KCNJ5	XM_011542810.4	c.1190A>G	p.Glu397Gly	missense_variant	Exon 3 of 3		XP_011541112.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KCNJ5	ENST00000529694.6	c.1190A>G	p.Glu397Gly	missense_variant	Exon 3 of 3	1	NM_000890.5	ENSP00000433295.1
KCNJ5	ENST00000338350.4	c.1190A>G	p.Glu397Gly	missense_variant	Exon 4 of 4	1		ENSP00000339960.4
KCNJ5	ENST00000533599.1	c.1190A>G	p.Glu397Gly	missense_variant	Exon 2 of 2	1		ENSP00000434266.1

Frequencies

GnomAD3 genomes AF: 0.0000263 AC: 4 AN: 152030 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000526 AC: 13 AN: 247338 AF XY: 0.0000521

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000380

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000123 AC: 18 AN: 1460450 Hom.: 0 Cov.: 32 AF XY: 0.0000138 AC XY: 10 AN XY: 726564

Gnomad4 AFR exome AF: 0.00 AC: 0 AN: 33296

Gnomad4 AMR exome AF: 0.000383 AC: 17 AN: 44374

Gnomad4 ASJ exome AF: 0.00 AC: 0 AN: 26046

Gnomad4 EAS exome AF: 0.00 AC: 0 AN: 39696

Gnomad4 SAS exome AF: 0.00 AC: 0 AN: 86180

Gnomad4 FIN exome AF: 0.00 AC: 0 AN: 53332

Gnomad4 NFE exome AF: 0.00 AC: 0 AN: 1111498

Gnomad4 Remaining exome AF: 0.0000166 AC: 1 AN: 60276

GnomAD4 genome AF: 0.0000263 AC: 4 AN: 152148 Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1 AN XY: 74388

Gnomad4 AFR AF: 0.00 AC: 0 AN: 0

Gnomad4 AMR AF: 0.000262 AC: 0.00026154 AN: 0.00026154

Gnomad4 ASJ AF: 0.00 AC: 0 AN: 0

Gnomad4 EAS AF: 0.00 AC: 0 AN: 0

Gnomad4 SAS AF: 0.00 AC: 0 AN: 0

Gnomad4 FIN AF: 0.00 AC: 0 AN: 0

Gnomad4 NFE AF: 0.00 AC: 0 AN: 0

Gnomad4 OTH AF: 0.00 AC: 0 AN: 0

Alfa AF: 0.0000434 Hom.: 0

Bravo AF: 0.0000340

ExAC AF: 0.0000247 AC: 3

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:2

Apr 17, 2017

Stanford Center for Inherited Cardiovascular Disease, Stanford University

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: provider interpretation

Found in a 7-year-old girl with a borderline QTc interval, and prolongation to 490 msec on exercise test, but no solid clinical diagnosis of LQTS. She had genetic testing for long QT syndrome with the Invitae laboratory. The following genes were evaluated for sequence changes and exonic deletions/duplications: AKAP9, ANK2, CACNA1C, CALM1, CALM2, CALM3, CAV3, KCNE1, KCNE2, KCNH2, KCNJ2, KCNJ5, KCNQ1, SCN4B, SCN5A, SNTA1, TRDN. One variant was detected: p.Glu397Gly (E397G; c.1190A>G) in exon 3 of the KCNJ5 gene (NM_000890.3) Chromosome position 11:128786556 A / G Based on the information reviewed below, we classify this as Variant of Uncertain Significance (VUS), concluding that there is not sufficient evidence for its pathogenicity to warrant using it for diagnosis or predictive genetic testing. We believe it is more likely to be a benign ethnicity-specific variant among Latinos. This variant has not been reported in the literature in association with disease. This is a non-conservative amino acid change, resulting in the replacement of a negatively-charged Glutamic Acid with a nonpolar Glycine. Glutamic Acid at this location is poorly conserved across vertebrate species (alternate amino acids include Lysine, Glutamine, Threonine, Serine, Aspartic Acid…). In fact, Glycine is the default amino acid in at least three species for which we have data. According to the Invitae report, algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies. This variant was reported in 13 individuals in the gnomAD database, and all of them have Latino ancestry like our patient. Latino allele frequency: 0.04% (~1 in 1280 people). It was not reported in any other ancestry group. This database includes variant calls on ~121,200 individuals of European, African, Latino, South Asian, Ashkenazi, and East Asian descent. The phenotype of those individuals is not publicly available. The dataset is comprised of multiple cohorts, some of which were recruited from the general population, others were enriched for common cardiovascular disease. The curators made an effort to exclude individuals with severe pediatric diseases. -

Jul 29, 2022

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Cardiovascular phenotype Uncertain:1

Nov 15, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.E397G variant (also known as c.1190A>G), located in coding exon 2 of the KCNJ5 gene, results from an A to G substitution at nucleotide position 1190. The glutamic acid at codon 397 is replaced by glycine, an amino acid with similar properties. This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Long QT syndrome Benign:1

May 08, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.068
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Benign	-0.33
CADD	Benign	17
DANN	Benign	0.95
DEOGEN2	Benign	0.26	T;T;T
Eigen	Benign	-0.54
Eigen_PC	Benign	-0.39
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.42	.;.;T
M_CAP	Uncertain	0.14	D
MetaRNN	Benign	0.13	T;T;T
MetaSVM	Benign	-0.76	T
MutationAssessor	Benign	0.90	L;L;L
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-0.53	N;N;N
REVEL	Benign	0.23
Sift	Benign	0.30	T;T;T
Sift4G	Benign	0.38	T;T;T
Polyphen		0.0	B;B;B
Vest4		0.065
MutPred		0.23		Loss of stability (P = 0.0519);Loss of stability (P = 0.0519);Loss of stability (P = 0.0519);
MVP		0.74
MPC		0.48
ClinPred		0.093	T
GERP RS		4.0
Varity_R		0.040
gMVP		0.27
Mutation Taster		=73/27	polymorphism

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: rs780934792; hg19: chr11-128786556;