rs761349623

Variant names:

• chr11-128911940-G-A
• rs761349623
• NM_000890.5:c.667G>A

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1 PM2 PP3_Moderate

The NM_000890.5(KCNJ5):​c.667G>A​(p.Asp223Asn) variant causes a missense change. The variant allele was found at a frequency of 0.00000207 in 1,447,134 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: KCNJ5 NM_000890.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.88

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_pathogenic. Variant got 6 ACMG points.

• PM1: In a topological_domain Cytoplasmic (size 233) in uniprot entity KCNJ5_HUMAN there are 5 pathogenic changes around while only 1 benign (83%) in NM_000890.5
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.854

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNJ5	NM_000890.5	c.667G>A	p.Asp223Asn	missense_variant	Exon 2 of 3	ENST00000529694.6	NP_000881.3
KCNJ5	NM_001354169.2	c.667G>A	p.Asp223Asn	missense_variant	Exon 3 of 4		NP_001341098.1
KCNJ5	XM_011542810.4	c.667G>A	p.Asp223Asn	missense_variant	Exon 2 of 3		XP_011541112.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KCNJ5	ENST00000529694.6	c.667G>A	p.Asp223Asn	missense_variant	Exon 2 of 3	1	NM_000890.5	ENSP00000433295.1
KCNJ5	ENST00000338350.4	c.667G>A	p.Asp223Asn	missense_variant	Exon 3 of 4	1		ENSP00000339960.4
KCNJ5	ENST00000533599.1	c.667G>A	p.Asp223Asn	missense_variant	Exon 1 of 2	1		ENSP00000434266.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000412 AC: 1 AN: 242656 Hom.: 0 AF XY: 0.00000765 AC XY: 1 AN XY: 130634

Gnomad AFR exome AF: 0.0000619

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS 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: 0.00000207 AC: 3 AN: 1447134 Hom.: 0 Cov.: 58 AF XY: 0.00000279 AC XY: 2 AN XY: 717550

Gnomad4 AFR exome AF: 0.0000302

Gnomad4 AMR 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: 0.00000181

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000756

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Long QT syndrome Uncertain:1

Sep 23, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ClinVar contains an entry for this variant (Variation ID: 221021). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on KCNJ5 function (PMID: 11278615, 34846128). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt KCNJ5 protein function. This variant has not been reported in the literature in individuals affected with KCNJ5-related conditions. This variant is present in population databases (rs761349623, gnomAD 0.007%). This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 223 of the KCNJ5 protein (p.Asp223Asn). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.90
BayesDel_addAF	Benign	-0.095	T
BayesDel_noAF	Benign	-0.19
CADD	Uncertain	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.77	D;D;D
Eigen	Uncertain	0.51
Eigen_PC	Uncertain	0.56
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.87	.;.;D
M_CAP	Benign	0.068	D
MetaRNN	Pathogenic	0.85	D;D;D
MetaSVM	Uncertain	0.25	D
MutationAssessor	Benign	1.5	L;L;L
PrimateAI	Pathogenic	0.82	D
PROVEAN	Benign	-2.2	N;N;N
REVEL	Uncertain	0.57
Sift	Benign	0.64	T;T;T
Sift4G	Benign	0.46	T;T;T
Polyphen		1.0	D;D;D
Vest4		0.56
MutPred		0.86		Gain of MoRF binding (P = 0.04);Gain of MoRF binding (P = 0.04);Gain of MoRF binding (P = 0.04);
MVP		0.95
MPC		1.2
ClinPred		0.98	D
GERP RS		5.5
Varity_R		0.27
gMVP		0.83

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: rs761349623; hg19: chr11-128781835; COSMIC: COSV100610658;