7-150958158-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 6P and 1B. PM1 PM2 PM5 BP4

The NM_000238.4(KCNH2):c.817C>G(p.Arg273Gly) 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. 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. R273Q) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: KCNH2 NM_000238.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.486

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 5 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 13 uncertain in NM_000238.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr7-150958157-C-T is described in Lovd as [Pathogenic].
• BP4: Computational evidence support a benign effect (MetaRNN=0.35905728).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KCNH2	NM_000238.4	c.817C>G	p.Arg273Gly	missense_variant	4/15	ENST00000262186.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KCNH2	ENST00000262186.10	c.817C>G	p.Arg273Gly	missense_variant	4/15	1	NM_000238.4	P1
KCNH2	ENST00000532957.5	n.1040C>G		non_coding_transcript_exon_variant	4/9	2
KCNH2	ENST00000684241.1	n.1650C>G		non_coding_transcript_exon_variant	2/13

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

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

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Aug 28, 2021

This sequence change replaces arginine with glycine at codon 273 of the KCNH2 protein (p.Arg273Gly). The arginine residue is weakly conserved and there is a moderate physicochemical difference between arginine and glycine. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate insufficient coverage at this position in the ExAC database. This variant has not been reported in the literature in individuals affected with KCNH2-related conditions. 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. 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
CardioboostArm	Benign	0.097
BayesDel_addAF	Pathogenic	0.20	D
BayesDel_noAF	Uncertain	0.060
Cadd	Benign	22
Dann	Benign	0.95
DEOGEN2	Uncertain	0.53	D;T
Eigen	Benign	-0.65
Eigen_PC	Benign	-0.59
FATHMM_MKL	Benign	0.37	N
LIST_S2	Benign	0.72	T;T
M_CAP	Pathogenic	0.92	D
MetaRNN	Benign	0.36	T;T
MetaSVM	Uncertain	0.67	D
MutationAssessor	Benign	1.4	L;.
MutationTaster	Benign	0.83	D;D;D
PrimateAI	Pathogenic	0.94	D
PROVEAN	Uncertain	-2.8	D;.
REVEL	Pathogenic	0.65
Sift	Uncertain	0.011	D;.
Sift4G	Benign	0.22	T;T
Polyphen		0.015	B;.
Vest4		0.19
MutPred		0.64		Loss of solvent accessibility (P = 0.0159);.;
MVP		0.93
MPC		1.3
ClinPred		0.36	T
GERP RS		1.8
Varity_R		0.23
gMVP		0.75

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: rs552583527; hg19: chr7-150655246;