rs199472881

chr7-150958103-A-Cchr7-150958103-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_000238.4(KCNH2):c.872T>G(p.Met291Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00000233 in 1,288,204 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic 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. M291T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000018 (0 hom.)
• Consequence: KCNH2 NM_000238.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:5
• Conservation: PhyloP100: 4.34

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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.78

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KCNH2	NM_000238.4	c.872T>G	p.Met291Arg	missense_variant	4/15	ENST00000262186.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KCNH2	ENST00000262186.10	c.872T>G	p.Met291Arg	missense_variant	4/15	1	NM_000238.4	P1
KCNH2	ENST00000532957.5	n.1095T>G		non_coding_transcript_exon_variant	4/9	2
KCNH2	ENST00000684241.1	n.1705T>G		non_coding_transcript_exon_variant	2/13

Frequencies

GnomAD3 genomes AF: 0.00000659 AC: 1 AN: 151790 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000656

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000176 AC: 2 AN: 1136414 Hom.: 0 Cov.: 31 AF XY: 0.00000184 AC XY: 1 AN XY: 542860

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000228

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: 0.00

GnomAD4 genome AF: 0.00000659 AC: 1 AN: 151790 Hom.: 0 Cov.: 33 AF XY: 0.0000135 AC XY: 1 AN XY: 74122

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.0000656

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000113

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Short QT syndrome type 1 Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Knight Diagnostic Laboratories, Oregon Health and Sciences University

Dec 04, 2015

- -

Long QT syndrome 2 Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Knight Diagnostic Laboratories, Oregon Health and Sciences University

Dec 04, 2015

- -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Athena Diagnostics

Jul 17, 2020

- -

Long QT syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Dec 14, 2023

This sequence change replaces methionine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 291 of the KCNH2 protein (p.Met291Arg). 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: 374955). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests 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. -

Short QT syndrome type 1;C3150943:Long QT syndrome 2 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 16, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.36
CardioboostArm	Uncertain	0.73
BayesDel_addAF	Pathogenic	0.29	D
BayesDel_noAF	Pathogenic	0.18
Cadd	Uncertain	25
Dann	Benign	0.96
DEOGEN2	Uncertain	0.51	D;T
Eigen	Uncertain	0.20
Eigen_PC	Uncertain	0.23
FATHMM_MKL	Uncertain	0.78	D
LIST_S2	Benign	0.70	T;T
M_CAP	Pathogenic	0.84	D
MetaRNN	Pathogenic	0.78	D;D
MetaSVM	Pathogenic	0.84	D
MutationAssessor	Benign	1.3	L;.
MutationTaster	Benign	0.93	D;D;D
PrimateAI	Pathogenic	0.98	D
PROVEAN	Benign	-1.9	N;.
REVEL	Pathogenic	0.77
Sift	Benign	0.15	T;.
Sift4G	Benign	0.34	T;T
Polyphen		0.96	D;.
Vest4		0.72
MutPred		0.42		Gain of solvent accessibility (P = 0.0021);.;
MVP		0.90
MPC		1.7
ClinPred		0.57	D
GERP RS		3.8
Varity_R		0.62
gMVP		0.81

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs199472881; hg19: chr7-150655191;