rs199473502

Variant names:

• chr7-150958213-G-C
• rs199473502
• NM_000238.4:c.762C>G

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 1P and 6B. PP2 BP4_Moderate BS2

The NM_000238.4(KCNH2):​c.762C>G​(p.His254Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000172 in 1,219,398 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign 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. H254Y) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.000017 (0 hom.)
• Consequence: KCNH2 NM_000238.4 missense
• Clinical Significance: not provided no classification provided O:1
• Conservation: PhyloP100: -0.553
• Publications: 3 publications found

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]

KCNH2 Gene-Disease associations (from GenCC):

• long QT syndrome

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• long QT syndrome 2

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P
• short QT syndrome

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen
• short QT syndrome type 1

  Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
• Brugada syndrome

  Inheritance: AD Classification: MODERATE, NO_KNOWN Submitted by: ClinGen, Genomics England PanelApp

ACMG classification

Our verdict: Likely_benign. The variant received -5 ACMG points.

• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 158 curated pathogenic missense variants (we use a threshold of 10). The gene has 38 curated benign missense variants. Gene score misZ: 3.3724 (above the threshold of 3.09). Trascript score misZ: 2.4846 (below the threshold of 3.09). GenCC associations: The gene is linked to long QT syndrome 2, Brugada syndrome, short QT syndrome type 1, short QT syndrome, long QT syndrome.
• BP4: Computational evidence support a benign effect (MetaRNN=0.20391327).
• BS2: High AC in GnomAdExome4 at 21 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNH2	NM_000238.4	c.762C>G	p.His254Gln	missense_variant	Exon 4 of 15	ENST00000262186.10	NP_000229.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KCNH2	ENST00000262186.10	c.762C>G	p.His254Gln	missense_variant	Exon 4 of 15	1	NM_000238.4	ENSP00000262186.5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.0000172 AC: 21 AN: 1219398 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 8 AN XY: 594508

African (AFR) AF: 0.00 AC: 0 AN: 24674

American (AMR) AF: 0.00 AC: 0 AN: 15644

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18654

East Asian (EAS) AF: 0.00 AC: 0 AN: 26730

South Asian (SAS) AF: 0.00 AC: 0 AN: 52906

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 29886

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3540

European-Non Finnish (NFE) AF: 0.0000211 AC: 21 AN: 997438

Other (OTH) AF: 0.00 AC: 0 AN: 49926

GnomAD4 genome Cov.: 33

ClinVar

Significance: not provided

Submissions summary: Other:1

Revision: no classification provided

Submissions by phenotype

not provided 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 in the following publications (PMID:14661677;PMID:19841300). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.084
CardioboostArm	Benign	0.0018
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Uncertain	-0.070
CADD	Benign	15
DANN	Benign	0.70
DEOGEN2	Benign	0.35	T;T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.075	N
LIST_S2	Benign	0.52	T;T
M_CAP	Pathogenic	0.87	D
MetaRNN	Benign	0.20	T;T
MetaSVM	Uncertain	0.21	D
MutationAssessor	Benign	0.55	N;.
PhyloP100		-0.55
PrimateAI	Pathogenic	0.85	D
PROVEAN	Benign	-1.0	N;.
REVEL	Uncertain	0.49
Sift	Benign	0.40	T;.
Sift4G	Benign	0.71	T;T
Polyphen		0.0010	B;.
Vest4		0.089
MutPred		0.43		Loss of methylation at R252 (P = 0.0578);.;
MVP		0.95
MPC		1.0
ClinPred		0.062	T
GERP RS		-1.3
Varity_R		0.051
gMVP		0.35
Mutation Taster		=85/15	polymorphism

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: rs199473502; hg19: chr7-150655301;