7-150948512-G-C

Variant names:

• chr7-150948512-G-C
• rs140743924
• NM_000238.4:c.2624C>G

Variant summary

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

The NM_000238.4(KCNH2):​c.2624C>G​(p.Thr875Arg) 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 benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. 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. T875M) has been classified as Benign.

• Frequency: Genomes: not found (cov: 31)
• Consequence: KCNH2 NM_000238.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.30

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=0.18613079).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNH2	NM_000238.4	c.2624C>G	p.Thr875Arg	missense_variant	Exon 11 of 15	ENST00000262186.10	NP_000229.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KCNH2	ENST00000262186.10	c.2624C>G	p.Thr875Arg	missense_variant	Exon 11 of 15	1	NM_000238.4	ENSP00000262186.5
KCNH2	ENST00000330883.9	c.1604C>G	p.Thr535Arg	missense_variant	Exon 7 of 11	1		ENSP00000328531.4
KCNH2	ENST00000684241.1	n.3457C>G		non_coding_transcript_exon_variant	Exon 9 of 13

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 37

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Long QT syndrome Uncertain:1

Apr 30, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with KCNH2-related conditions. ClinVar contains an entry for this variant (Variation ID: 849676). 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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. 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. This sequence change replaces threonine, which is neutral and polar, with arginine, which is basic and polar, at codon 875 of the KCNH2 protein (p.Thr875Arg). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Uncertain	0.14	D
BayesDel_noAF	Uncertain	-0.030
CADD	Benign	21
DANN	Benign	0.87
DEOGEN2	Benign	0.31	.;T
Eigen	Benign	-0.59
Eigen_PC	Benign	-0.56
FATHMM_MKL	Benign	0.15	N
LIST_S2	Benign	0.21	T;T
M_CAP	Pathogenic	0.56	D
MetaRNN	Benign	0.19	T;T
MetaSVM	Uncertain	0.51	D
MutationAssessor	Benign	0.69	.;N
PrimateAI	Benign	0.40	T
PROVEAN	Benign	-0.15	N;N
REVEL	Uncertain	0.42
Sift	Benign	0.49	T;T
Sift4G	Benign	0.57	T;T
Polyphen		0.80	P;B
Vest4		0.25
MutPred		0.27		.;Loss of phosphorylation at T875 (P = 0.0138);
MVP		0.85
MPC		0.19
ClinPred		0.20	T
GERP RS		4.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.3
Varity_R		0.055
gMVP		0.68

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs140743924; hg19: chr7-150645600;