7-150948476-C-G

Variant names:

• chr7-150948476-C-G
• rs199473432
• NM_000238.4:c.2660G>C

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM2 PM5 PP2

The NM_000238.4(KCNH2):​c.2660G>C​(p.Arg887Pro) variant causes a missense change. The variant allele was found at a frequency of 0.00000072 in 1,389,090 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. R887H) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 7.2e-7 (0 hom.)
• Consequence: KCNH2 NM_000238.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.36
• Publications: 8 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: Uncertain_significance. The variant received 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr7-150948476-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 67423.
• 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNH2	NM_000238.4	c.2660G>C	p.Arg887Pro	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.2660G>C	p.Arg887Pro	missense_variant	Exon 11 of 15	1	NM_000238.4	ENSP00000262186.5

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 7.20e-7 AC: 1 AN: 1389090 Hom.: 0 Cov.: 37 AF XY: 0.00 AC XY: 0 AN XY: 691360

African (AFR) AF: 0.00 AC: 0 AN: 31132

American (AMR) AF: 0.00 AC: 0 AN: 42618

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23504

East Asian (EAS) AF: 0.00 AC: 0 AN: 32758

South Asian (SAS) AF: 0.00 AC: 0 AN: 85654

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 42160

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5436

European-Non Finnish (NFE) AF: 9.34e-7 AC: 1 AN: 1070240

Other (OTH) AF: 0.00 AC: 0 AN: 55588

GnomAD4 genome Cov.: 31

Alfa AF: 0.0000181 Hom.: 0

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Cardiovascular phenotype Uncertain:1

Oct 04, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.R887P variant (also known as c.2660G>C), located in coding exon 11 of the KCNH2 gene, results from a G to C substitution at nucleotide position 2660. The arginine at codon 887 is replaced by proline, an amino acid with dissimilar properties. This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, the clinical significance of this variant remains unclear.

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.56
CardioboostArm	Benign	0.012
BayesDel_addAF	Pathogenic	0.43	D
BayesDel_noAF	Pathogenic	0.39
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.0	.;D
Eigen	Benign	0.12
Eigen_PC	Benign	0.14
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Uncertain	0.87	D;D
M_CAP	Pathogenic	0.90	D
MetaRNN	Uncertain	0.51	D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Benign	0.0	.;L
PhyloP100		4.4
PrimateAI	Uncertain	0.60	T
PROVEAN	Uncertain	-2.9	D;D
REVEL	Pathogenic	0.78
Sift	Benign	0.044	D;D
Sift4G	Benign	0.23	T;T
Vest4		0.40
ClinPred		0.98	D
GERP RS		4.1
Varity_R		0.73
gMVP		0.89
Mutation Taster		=6/94	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: rs199473432; hg19: chr7-150645564;