11-128911725-G-A

Position:

• chr11-128911725-G-A

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM2 PP3_Strong PP5_Moderate

The NM_000890.5(KCNJ5):​c.452G>A​(p.Gly151Glu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: KCNJ5 NM_000890.5 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 8.01

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 8 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.996
• PP5: Variant 11-128911725-G-A is Pathogenic according to our data. Variant chr11-128911725-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 135679.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr11-128911725-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KCNJ5	NM_000890.5	c.452G>A	p.Gly151Glu	missense_variant	2/3	ENST00000529694.6	NP_000881.3
KCNJ5	NM_001354169.2	c.452G>A	p.Gly151Glu	missense_variant	3/4		NP_001341098.1
KCNJ5	XM_011542810.4	c.452G>A	p.Gly151Glu	missense_variant	2/3		XP_011541112.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KCNJ5	ENST00000529694.6	c.452G>A	p.Gly151Glu	missense_variant	2/3	1	NM_000890.5	ENSP00000433295.1
KCNJ5	ENST00000338350.4	c.452G>A	p.Gly151Glu	missense_variant	3/4	1		ENSP00000339960.4
KCNJ5	ENST00000533599.1	c.452G>A	p.Gly151Glu	missense_variant	1/2	1		ENSP00000434266.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 58

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Familial hyperaldosteronism type III Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Feb 14, 2012

- -

Long QT syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Aug 22, 2019

For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Gly151 amino acid residue in KCNJ5. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 22308486, 24819081). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. This variant has been reported to affect KCNJ5 protein function (PMID: 22203740, 22308486). This variant has been observed to segregate with hyperaldosteronism in families (PMID: 22203740, 22308486). ClinVar contains an entry for this variant (Variation ID: 135679). This variant is not present in population databases (ExAC no frequency). This sequence change replaces glycine with glutamic acid at codon 151 of the KCNJ5 protein (p.Gly151Glu). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and glutamic acid. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.55	D
BayesDel_noAF	Pathogenic	0.56
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.98	D;D;D
Eigen	Pathogenic	0.71
Eigen_PC	Uncertain	0.58
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	.;.;D
M_CAP	Pathogenic	0.67	D
MetaRNN	Pathogenic	1.0	D;D;D
MetaSVM	Pathogenic	0.89	D
MutationAssessor	Pathogenic	4.0	H;H;H
PrimateAI	Pathogenic	0.88	D
PROVEAN	Pathogenic	-7.7	D;D;D
REVEL	Pathogenic	0.95
Sift	Pathogenic	0.0	D;D;D
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		1.0	D;D;D
Vest4		0.99
MutPred		0.99		Loss of catalytic residue at Y152 (P = 0.0826);Loss of catalytic residue at Y152 (P = 0.0826);Loss of catalytic residue at Y152 (P = 0.0826);
MVP		0.96
MPC		1.4
ClinPred		1.0	D
GERP RS		4.5
Varity_R		0.95
gMVP		1.0

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: rs587777437; hg19: chr11-128781620;