7-150958221-G-C

Variant names:

• chr7-150958221-G-C
• rs199472874
• NM_000238.4:c.754C>G

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 1P and 2B. PP2 BP4 BS2_Supporting

The NM_000238.4(KCNH2):​c.754C>G​(p.Arg252Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000437 in 1,371,584 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. R252P) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: KCNH2 NM_000238.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1 O:1
• Conservation: PhyloP100: 1.14
• Publications: 4 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 -1 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=0.39034152).
• BS2: High AC in GnomAdExome4 at 5 AD gene. Variant has AC lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000238.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCNH2	NM_000238.4	MANE Select	c.754C>G	p.Arg252Gly	missense	Exon 4 of 15	NP_000229.1
	KCNH2	NM_001406753.1		c.466C>G	p.Arg156Gly	missense	Exon 2 of 13	NP_001393682.1
	KCNH2	NM_172056.3		c.754C>G	p.Arg252Gly	missense	Exon 4 of 9	NP_742053.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCNH2	ENST00000262186.10	TSL:1 MANE Select	c.754C>G	p.Arg252Gly	missense	Exon 4 of 15	ENSP00000262186.5
	KCNH2	ENST00000713710.1		c.754C>G	p.Arg252Gly	missense	Exon 4 of 15	ENSP00000519013.1
	KCNH2	ENST00000713701.1		c.454C>G	p.Arg152Gly	missense	Exon 3 of 14	ENSP00000519004.1

Frequencies

GnomAD3 genomes AF: 0.00000659 AC: 1 AN: 151846 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: 0.00000410 AC: 5 AN: 1219738 Hom.: 0 Cov.: 31 AF XY: 0.00000336 AC XY: 2 AN XY: 594704

African (AFR) AF: 0.0000405 AC: 1 AN: 24680

American (AMR) AF: 0.00 AC: 0 AN: 15396

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18662

East Asian (EAS) AF: 0.00 AC: 0 AN: 26756

South Asian (SAS) AF: 0.00 AC: 0 AN: 53040

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 29940

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3550

European-Non Finnish (NFE) AF: 0.00000401 AC: 4 AN: 997778

Other (OTH) AF: 0.00 AC: 0 AN: 49936

GnomAD4 genome AF: 0.00000659 AC: 1 AN: 151846 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 74182

African (AFR) AF: 0.00 AC: 0 AN: 41396

American (AMR) AF: 0.0000656 AC: 1 AN: 15236

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10492

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67916

Other (OTH) AF: 0.00 AC: 0 AN: 2086

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1 Other:1

Revision: criteria provided, single submitter

Submissions by phenotype

Long QT syndrome Uncertain:1

Jan 21, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with glycine, which is neutral and non-polar, at codon 252 of the KCNH2 protein (p.Arg252Gly). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with long QT syndrome (PMID: 17088455). ClinVar contains an entry for this variant (Variation ID: 67524). 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.

Congenital long QT syndrome 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 as associated with Long QT syndrome in the following publications (PMID:19926013). This is a literature report, and does not necessarily reflect the clinical interpretation of the Imperial College / Royal Brompton Cardiovascular Genetics laboratory.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.075
CardioboostArm	Benign	0.0076
BayesDel_addAF	Pathogenic	0.39	D
BayesDel_noAF	Pathogenic	0.33
CADD	Benign	18
DANN	Benign	0.95
DEOGEN2	Benign	0.38	T
Eigen	Benign	-0.82
Eigen_PC	Benign	-0.88
FATHMM_MKL	Benign	0.19	N
LIST_S2	Benign	0.75	T
M_CAP	Pathogenic	0.81	D
MetaRNN	Benign	0.39	T
MetaSVM	Uncertain	0.45	D
MutationAssessor	Benign	0.69	N
PhyloP100		1.1
PrimateAI	Pathogenic	0.87	D
PROVEAN	Benign	-1.4	N
REVEL	Uncertain	0.57
Sift	Uncertain	0.015	D
Sift4G	Benign	0.11	T
Polyphen		0.015	B
Vest4		0.19
MutPred		0.76		Loss of methylation at R252 (P = 0.0085)
MVP		1.0
MPC		1.7
ClinPred		0.14	T
GERP RS		1.3
Varity_R		0.10
gMVP		0.46
Mutation Taster		=33/67	disease causing

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

Other links and lift over

dbSNP: rs199472874; hg19: chr7-150655309;