rs199472867

Variant names:

• chr7-150958416-C-A
• NM_000238.4:c.559G>T

Your query was ambiguous. Multiple possible variants found:

• chr7-150958416-C-A
• chr7-150958416-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_000238.4(KCNH2):​c.559G>T​(p.Gly187Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000777 in 1,286,284 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. G187S) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.8e-7 (0 hom.)
• Consequence: KCNH2 NM_000238.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.431

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 Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNH2	NM_000238.4	c.559G>T	p.Gly187Cys	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.559G>T	p.Gly187Cys	missense_variant	Exon 4 of 15	1	NM_000238.4	ENSP00000262186.5
KCNH2	ENST00000532957.5	n.782G>T		non_coding_transcript_exon_variant	Exon 4 of 9	2
KCNH2	ENST00000684241.1	n.1392G>T		non_coding_transcript_exon_variant	Exon 2 of 13

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 7.77e-7 AC: 1 AN: 1286284 Hom.: 0 Cov.: 32 AF XY: 0.00000158 AC XY: 1 AN XY: 633232

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000188

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Long QT syndrome Uncertain:1

Dec 02, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. This variant has not been reported in the literature in individuals affected with KCNH2-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glycine, which is neutral and non-polar, with cysteine, which is neutral and slightly polar, at codon 187 of the KCNH2 protein (p.Gly187Cys). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Uncertain	-0.070
CADD	Benign	7.8
DANN	Uncertain	0.98
DEOGEN2	Benign	0.41	T
Eigen	Benign	-0.75
Eigen_PC	Benign	-0.89
FATHMM_MKL	Benign	0.11	N
LIST_S2	Benign	0.68	T
M_CAP	Pathogenic	0.85	D
MetaRNN	Uncertain	0.50	T
MetaSVM	Uncertain	0.69	D
MutationAssessor	Benign	1.2	L
PrimateAI	Uncertain	0.74	T
PROVEAN	Benign	-1.7	N
REVEL	Uncertain	0.50
Sift	Uncertain	0.024	D
Sift4G	Benign	0.23	T
Polyphen		0.88	P
Vest4		0.36
MutPred		0.34		Loss of disorder (P = 0.0444);
MVP		0.82
MPC		1.5
ClinPred		0.20	T
GERP RS		0.38
Varity_R		0.091
gMVP		0.38

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr7-150655504;