rs199472860

Variant names:

• chr7-150959712-T-A
• rs199472860
• NM_000238.4:c.332A>T

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1 PM2 PP3_Strong

The NM_000238.4(KCNH2):​c.332A>T​(p.Asp111Val) variant causes a missense change. 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 not provided (no stars).

• Frequency: Genomes: not found (cov: 33)
• Consequence: KCNH2 NM_000238.4 missense
• Clinical Significance: not provided no classification provided O:1
• Conservation: PhyloP100: 4.68

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 8 ACMG points.

• PM1: In a domain PAC (size 52) in uniprot entity KCNH2_HUMAN there are 11 pathogenic changes around while only 1 benign (92%) in NM_000238.4
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.973

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNH2	NM_000238.4	c.332A>T	p.Asp111Val	missense_variant	Exon 3 of 15	ENST00000262186.10	NP_000229.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KCNH2	ENST00000262186.10	c.332A>T	p.Asp111Val	missense_variant	Exon 3 of 15	1	NM_000238.4	ENSP00000262186.5
KCNH2	ENST00000532957.5	n.555A>T		non_coding_transcript_exon_variant	Exon 3 of 9	2
KCNH2	ENST00000684241.1	n.1165A>T		non_coding_transcript_exon_variant	Exon 1 of 13

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: not provided

Submissions summary: Other:1

Revision: no classification provided

Submissions by phenotype

Congenital long QT syndrome Other:1

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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:18441445;PMID:20975234). 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	Pathogenic	0.96
BayesDel_addAF	Pathogenic	0.45	D
BayesDel_noAF	Pathogenic	0.41
CADD	Pathogenic	28
DANN	Uncertain	0.98
DEOGEN2	Pathogenic	0.92	D;D
Eigen	Benign	-0.0089
Eigen_PC	Benign	0.13
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.97	D;D
M_CAP	Pathogenic	0.81	D
MetaRNN	Pathogenic	0.97	D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Benign	1.7	L;.
PrimateAI	Pathogenic	0.85	D
PROVEAN	Pathogenic	-4.5	D;.
REVEL	Pathogenic	0.80
Sift	Benign	0.40	T;.
Sift4G	Benign	0.61	T;T
Polyphen		0.051	B;.
Vest4		0.92
MutPred		0.85		Loss of sheet (P = 0.0457);.;
MVP		0.99
MPC		2.3
ClinPred		0.97	D
GERP RS		4.8
Varity_R		0.90
gMVP		0.98

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs199472860; hg19: chr7-150656800;