rs1057517742

Variant names:

• chr7-150958430-G-A
• rs1057517742
• NM_000238.4:c.545C>T

Your query was ambiguous. Multiple possible variants found:

• chr7-150958430-G-A
• chr7-150958430-G-C
• chr7-150958430-G-T

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 1P and 6B. PP2 BP4_Moderate BS2

The NM_000238.4(KCNH2):​c.545C>T​(p.Ser182Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000069 in 1,305,082 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/23 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. S182W) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000069 (0 hom.)
• Consequence: KCNH2 NM_000238.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.622
• Publications: 2 publications found

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]

KCNH2 Gene-Disease associations (from GenCC):

• long QT syndrome

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• long QT syndrome 2

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P
• short QT syndrome

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen
• short QT syndrome type 1

  Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
• Brugada syndrome

  Inheritance: AD Classification: MODERATE, NO_KNOWN Submitted by: ClinGen, Genomics England PanelApp

ACMG classification

Our verdict: Likely_benign. The variant received -5 ACMG points.

• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 158 curated pathogenic missense variants (we use a threshold of 10). The gene has 38 curated benign missense variants. Gene score misZ: 3.3724 (above the threshold of 3.09). Trascript score misZ: 2.4846 (below the threshold of 3.09). GenCC associations: The gene is linked to long QT syndrome 2, Brugada syndrome, short QT syndrome type 1, short QT syndrome, long QT syndrome.
• BP4: Computational evidence support a benign effect (MetaRNN=0.18554452).
• BS2: High AC in GnomAdExome4 at 9 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNH2	NM_000238.4	c.545C>T	p.Ser182Leu	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.545C>T	p.Ser182Leu	missense_variant	Exon 4 of 15	1	NM_000238.4	ENSP00000262186.5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000690 AC: 9 AN: 1305082 Hom.: 0 Cov.: 32 AF XY: 0.00000933 AC XY: 6 AN XY: 643168

African (AFR) AF: 0.00 AC: 0 AN: 26144

American (AMR) AF: 0.00 AC: 0 AN: 23412

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 22318

East Asian (EAS) AF: 0.00 AC: 0 AN: 28310

South Asian (SAS) AF: 0.00 AC: 0 AN: 70218

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 32622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4140

European-Non Finnish (NFE) AF: 0.00000862 AC: 9 AN: 1043996

Other (OTH) AF: 0.00 AC: 0 AN: 53922

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000113

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Long QT syndrome Uncertain:1

Dec 21, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 182 of the KCNH2 protein (p.Ser182Leu). 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. 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	0.090
CardioboostArm	Benign	0.0000074
BayesDel_addAF	Benign	0.00013	T
BayesDel_noAF	Benign	-0.24
CADD	Benign	17
DANN	Benign	0.96
DEOGEN2	Benign	0.36	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.42	N
LIST_S2	Benign	0.80	T
M_CAP	Pathogenic	0.40	D
MetaRNN	Benign	0.19	T
MetaSVM	Uncertain	0.56	D
MutationAssessor	Benign	0.69	N
PhyloP100		0.62
PrimateAI	Uncertain	0.73	T
PROVEAN	Benign	-1.0	N
REVEL	Uncertain	0.44
Sift	Benign	0.15	T
Sift4G	Benign	0.30	T
Polyphen		0.024	B
Vest4		0.17
MutPred		0.39		Loss of glycosylation at S182 (P = 0.004);
MVP		0.54
MPC		0.91
ClinPred		0.074	T
GERP RS		1.7
Varity_R		0.037
gMVP		0.32
Mutation Taster		=88/12	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1057517742; hg19: chr7-150655518; COSMIC: COSV51211356; COSMIC: COSV51211356;