7-150958416-C-T

Variant names:

• chr7-150958416-C-T
• rs199472867
• NM_000238.4:c.559G>A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_000238.4(KCNH2):​c.559G>A​(p.Gly187Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000155 in 1,286,284 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as not provided (no stars).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000016 (0 hom.)
• Consequence: KCNH2 NM_000238.4 missense
• Clinical Significance: not provided no classification provided O: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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.13397789).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNH2	NM_000238.4	c.559G>A	p.Gly187Ser	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>A	p.Gly187Ser	missense_variant	Exon 4 of 15	1	NM_000238.4	ENSP00000262186.5
KCNH2	ENST00000532957.5	n.782G>A		non_coding_transcript_exon_variant	Exon 4 of 9	2
KCNH2	ENST00000684241.1	n.1392G>A		non_coding_transcript_exon_variant	Exon 2 of 13

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000155 AC: 2 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: 0.0000151

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.64e-7

Gnomad4 OTH exome AF: 0.00

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	0.076
BayesDel_addAF	Benign	0.0050	T
BayesDel_noAF	Benign	-0.23
CADD	Benign	5.3
DANN	Benign	0.89
DEOGEN2	Benign	0.33	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.024	N
LIST_S2	Benign	0.65	T
M_CAP	Pathogenic	0.48	D
MetaRNN	Benign	0.13	T
MetaSVM	Uncertain	0.35	D
MutationAssessor	Benign	1.2	L
PrimateAI	Uncertain	0.72	T
PROVEAN	Benign	-0.48	N
REVEL	Uncertain	0.31
Sift	Benign	0.44	T
Sift4G	Benign	0.71	T
Polyphen		0.0020	B
Vest4		0.085
MutPred		0.21		Gain of glycosylation at G187 (P = 0.0167);
MVP		0.71
MPC		1.0
ClinPred		0.032	T
GERP RS		0.38
Varity_R		0.027
gMVP		0.31

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: rs199472867; hg19: chr7-150655504;