11-128911712-G-C

Variant names:

• chr11-128911712-G-C
• rs148355179
• NM_000890.5:c.439G>C

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM1 PM2 PP3_Moderate

The NM_000890.5(KCNJ5):​c.439G>C​(p.Glu147Gln) 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. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E147K) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: KCNJ5 NM_000890.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.01
• 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 Gene-Disease associations (from GenCC):

• familial hyperaldosteronism type III

  Inheritance: AD Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Ambry Genetics, Orphanet, Labcorp Genetics (formerly Invitae)
• Andersen-Tawil syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• long QT syndrome 13

  Inheritance: AD Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
• long QT syndrome

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 7 uncertain in NM_000890.5
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.922

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNJ5	NM_000890.5	c.439G>C	p.Glu147Gln	missense_variant	Exon 2 of 3	ENST00000529694.6	NP_000881.3
KCNJ5	NM_001354169.2	c.439G>C	p.Glu147Gln	missense_variant	Exon 3 of 4		NP_001341098.1
KCNJ5	XM_011542810.4	c.439G>C	p.Glu147Gln	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.439G>C	p.Glu147Gln	missense_variant	Exon 2 of 3	1	NM_000890.5	ENSP00000433295.1
KCNJ5	ENST00000338350.4	c.439G>C	p.Glu147Gln	missense_variant	Exon 3 of 4	1		ENSP00000339960.4
KCNJ5	ENST00000533599.1	c.439G>C	p.Glu147Gln	missense_variant	Exon 1 of 2	1		ENSP00000434266.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 59

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Long QT syndrome Uncertain:1

Jun 19, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. 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 expected to disrupt KCNJ5 protein function. This variant has not been reported in the literature in individuals with KCNJ5-related conditions. This variant is not present in population databases (ExAC no frequency). This sequence change replaces glutamic acid with glutamine at codon 147 of the KCNJ5 protein (p.Glu147Gln). The glutamic acid residue is highly conserved and there is a small physicochemical difference between glutamic acid and glutamine.

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.74
BayesDel_addAF	Pathogenic	0.34	D
BayesDel_noAF	Pathogenic	0.25
CADD	Uncertain	24
DANN	Benign	0.61
DEOGEN2	Uncertain	0.60	D;D;D
Eigen	Benign	0.14
Eigen_PC	Benign	0.20
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.0	.;.;T
M_CAP	Uncertain	0.21	D
MetaRNN	Pathogenic	0.92	D;D;D
MetaSVM	Uncertain	0.26	D
MutationAssessor	Benign	0.28	N;N;N
PhyloP100		8.0
PrimateAI	Pathogenic	0.83	D
PROVEAN	Benign	-0.95	N;N;N
REVEL	Uncertain	0.61
Sift	Benign	1.0	T;T;T
Sift4G	Benign	1.0	T;T;T
Vest4		0.86
ClinPred		0.40	T
GERP RS		5.5
Varity_R		0.23
gMVP		0.97
Mutation Taster		=50/50

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

Other links and lift over

dbSNP: rs148355179; hg19: chr11-128781607;