7-150958319-T-A

Position:

• chr7-150958319-T-A

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS2

The ENST00000262186.10(KCNH2):​c.656A>T​(p.Asp219Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000823 in 1,335,844 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D219N) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000082 (0 hom.)
• Consequence: KCNH2 ENST00000262186.10 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts P:1 U:2
• Conservation: PhyloP100: 0.936

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_benign. Variant got -4 ACMG points.

• BS2: High AC in GnomAdExome4 at 11 AD,Digenic gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KCNH2	NM_000238.4	c.656A>T	p.Asp219Val	missense_variant	4/15	ENST00000262186.10	NP_000229.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KCNH2	ENST00000262186.10	c.656A>T	p.Asp219Val	missense_variant	4/15	1	NM_000238.4	ENSP00000262186	P1
KCNH2	ENST00000532957.5	n.879A>T		non_coding_transcript_exon_variant	4/9	2
KCNH2	ENST00000684241.1	n.1489A>T		non_coding_transcript_exon_variant	2/13

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.0000201 AC: 2 AN: 99608 Hom.: 0 AF XY: 0.0000177 AC XY: 1 AN XY: 56470

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000111

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000823 AC: 11 AN: 1335844 Hom.: 0 Cov.: 32 AF XY: 0.0000121 AC XY: 8 AN XY: 659906

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000338

Gnomad4 SAS exome AF: 0.000135

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ExAC AF: 0.0000196 AC: 2

Asia WGS AF: 0.000889 AC: 3 AN: 3390

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1 Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Long QT syndrome Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Mar 13, 2022	This sequence change replaces aspartic acid, which is acidic and polar, with valine, which is neutral and non-polar, at codon 219 of the KCNH2 protein (p.Asp219Val). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with long QT syndrome (PMID: 25914329). ClinVar contains an entry for this variant (Variation ID: 157662). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). Experimental studies have shown that this missense change affects KCNH2 function (PMID: 25914329). 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. -
Uncertain significance, criteria provided, single submitter	research	Dept of Medical Biology, Uskudar University	Jan 08, 2024	Criteria: PM2, PP2 -

Long QT syndrome 2 Pathogenic:1

Pathogenic, no assertion criteria provided

research

McDonald Lab; Albert Einstein College of Medicine

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.30
BayesDel_addAF	Pathogenic	0.18	D
BayesDel_noAF	Uncertain	0.020
CADD	Benign	22
DANN	Benign	0.90
DEOGEN2	Benign	0.36	T;T
Eigen	Benign	-0.20
Eigen_PC	Benign	-0.10
FATHMM_MKL	Uncertain	0.77	D
LIST_S2	Benign	0.85	T;D
M_CAP	Pathogenic	0.95	D
MetaRNN	Uncertain	0.46	T;T
MetaSVM	Uncertain	0.51	D
MutationAssessor	Benign	0.69	N;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Pathogenic	0.88	D
PROVEAN	Benign	-1.5	N;.
REVEL	Uncertain	0.60
Sift	Benign	0.092	T;.
Sift4G	Benign	0.54	T;T
Polyphen		0.65	P;.
Vest4		0.47
MutPred		0.37		Gain of glycosylation at T216 (P = 0.0856);.;
MVP		0.88
MPC		1.4
ClinPred		0.31	T
GERP RS		3.4
Varity_R		0.32
gMVP		0.55

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: rs587777907; hg19: chr7-150655407;