11-128911712-G-C

Position:

• chr11-128911712-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. 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 (★).

• 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

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 Uncertain_significance. Variant got 4 ACMG points.

• 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/exons	MANE	Protein	UniProt
KCNJ5	NM_000890.5	c.439G>C	p.Glu147Gln	missense_variant	2/3	ENST00000529694.6	NP_000881.3
KCNJ5	NM_001354169.2	c.439G>C	p.Glu147Gln	missense_variant	3/4		NP_001341098.1
KCNJ5	XM_011542810.4	c.439G>C	p.Glu147Gln	missense_variant	2/3		XP_011541112.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KCNJ5	ENST00000529694.6	c.439G>C	p.Glu147Gln	missense_variant	2/3	1	NM_000890.5	ENSP00000433295.1
KCNJ5	ENST00000338350.4	c.439G>C	p.Glu147Gln	missense_variant	3/4	1		ENSP00000339960.4
KCNJ5	ENST00000533599.1	c.439G>C	p.Glu147Gln	missense_variant	1/2	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

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jun 19, 2021

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. This variant has not been reported in the literature in individuals with KCNJ5-related conditions. 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. -

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	0.85	.;.;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
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
Polyphen		1.0	D;D;D
Vest4		0.86
MutPred		0.74		Loss of sheet (P = 0.0817);Loss of sheet (P = 0.0817);Loss of sheet (P = 0.0817);
MVP		0.93
MPC		1.2
ClinPred		0.40	T
GERP RS		5.5
Varity_R		0.23
gMVP		0.97

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr11-128781607; COSMIC: COSV57971312;