rs199473496

Variant names:

• chr7-150974732-T-C
• rs199473496
• NM_000238.4:c.286A>G

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1 PM2 PM5

The NM_000238.4(KCNH2):​c.286A>G​(p.Ile96Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as not provided (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I96T) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 34)
• Consequence: KCNH2 NM_000238.4 missense
• Clinical Significance: not provided no classification provided O:1
• Conservation: PhyloP100: 3.34

Genes affected

KCNH2 (HGNC:6251): (potassium voltage-gated channel subfamily H member 2) This gene encodes a component of a voltage-activated potassium channel found in cardiac muscle, nerve cells, and microglia. Four copies of this protein interact with one copy of the KCNE2 protein to form a functional potassium channel. Mutations in this gene can cause long QT syndrome type 2 (LQT2). Transcript variants encoding distinct isoforms have been identified. [provided by RefSeq, May 2022]

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM1: In a strand (size 7) in uniprot entity KCNH2_HUMAN there are 4 pathogenic changes around while only 0 benign (100%) in NM_000238.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr7-150974731-A-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNH2	NM_000238.4	c.286A>G	p.Ile96Val	missense_variant	Exon 2 of 15	ENST00000262186.10	NP_000229.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KCNH2	ENST00000262186.10	c.286A>G	p.Ile96Val	missense_variant	Exon 2 of 15	1	NM_000238.4	ENSP00000262186.5
KCNH2	ENST00000532957.5	n.509A>G		non_coding_transcript_exon_variant	Exon 2 of 9	2

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 34

ClinVar

Significance: not provided

Submissions summary: Other:1

Revision: no classification provided

Submissions by phenotype

Congenital long QT syndrome Other:1

-

Cardiovascular Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

This variant has been reported as associated with Long QT syndrome in the following publications (PMID:19841300). This is a literature report, and does not necessarily reflect the clinical interpretation of the Imperial College / Royal Brompton Cardiovascular Genetics laboratory. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Uncertain	0.087	D
BayesDel_noAF	Benign	-0.11
CADD	Uncertain	23
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.62	D;D
Eigen	Benign	-0.39
Eigen_PC	Benign	-0.28
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Uncertain	0.87	D;D
M_CAP	Pathogenic	0.82	D
MetaRNN	Uncertain	0.57	D;D
MetaSVM	Pathogenic	0.88	D
MutationAssessor	Benign	1.5	L;.
PrimateAI	Pathogenic	0.86	D
PROVEAN	Benign	-0.42	N;.
REVEL	Uncertain	0.43
Sift	Benign	0.37	T;.
Sift4G	Benign	0.35	T;T
Polyphen		0.0040	B;.
Vest4		0.39
MutPred		0.79		Gain of sheet (P = 0.0221);.;
MVP		0.69
MPC		1.2
ClinPred		0.60	D
GERP RS		3.2
Varity_R		0.082
gMVP		0.85

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: rs199473496; hg19: chr7-150671820;