rs199473418

chr7-150974810-G-T

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1 PM2 PM5 PP3_Strong

The NM_000238.4(KCNH2):c.208C>A(p.His70Asn) variant causes a missense change involving the alteration of a non-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 not provided (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H70R) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 34)
• Consequence: KCNH2 NM_000238.4 missense
• Clinical Significance: not provided no classification provided O:1
• Conservation: PhyloP100: 1.85

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 Pathogenic. Variant got 10 ACMG points.

• PM1: In a hotspot region, there are 10 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 15 uncertain 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 chr7-150974809-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 67363.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.94

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KCNH2	NM_000238.4	c.208C>A	p.His70Asn	missense_variant	2/15	ENST00000262186.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KCNH2	ENST00000262186.10	c.208C>A	p.His70Asn	missense_variant	2/15	1	NM_000238.4	P1
KCNH2	ENST00000532957.5	n.431C>A		non_coding_transcript_exon_variant	2/9	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

not provided, no classification provided

literature only

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

-

This variant has been reported as associated with Long QT syndrome in the following publications (PMID:19716085). 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	0.29
CardioboostArm	Benign	0.0062
BayesDel_addAF	Uncertain	0.16	D
BayesDel_noAF	Uncertain	-0.010
Cadd	Pathogenic	29
Dann	Benign	0.85
DEOGEN2	Uncertain	0.76	D;D
Eigen	Benign	-0.24
Eigen_PC	Benign	-0.26
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Uncertain	0.95	D;D
M_CAP	Pathogenic	0.93	D
MetaRNN	Pathogenic	0.94	D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Benign	1.8	L;.
MutationTaster	Benign	0.81	N;N
PrimateAI	Pathogenic	0.92	D
PROVEAN	Benign	-2.2	N;.
REVEL	Pathogenic	0.70
Sift	Benign	0.13	T;.
Sift4G	Benign	0.16	T;D
Polyphen		0.95	P;.
Vest4		0.72
MutPred		0.80		Gain of relative solvent accessibility (P = 0.0289);.;
MVP		0.89
MPC		2.2
ClinPred		0.48	T
GERP RS		3.5
Varity_R		0.73
gMVP		0.95

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: rs199473418; hg19: chr7-150671898;