NM_000238.4:c.3007G>C

Variant names:

• chr7-150947473-C-G
• rs794728402
• NM_000238.4:c.3007G>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.3007G>C​(p.Asp1003His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000211 in 1,424,968 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D1003Y) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: KCNH2 NM_000238.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.66
• Publications: 0 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 chr7-150947473-C-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 200516.
• 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.3007G>C	p.Asp1003His	missense_variant	Exon 13 of 15	ENST00000262186.10	NP_000229.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KCNH2	ENST00000262186.10	c.3007G>C	p.Asp1003His	missense_variant	Exon 13 of 15	1	NM_000238.4	ENSP00000262186.5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000535 AC: 1 AN: 186764 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000366

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000211 AC: 3 AN: 1424968 Hom.: 0 Cov.: 36 AF XY: 0.00000142 AC XY: 1 AN XY: 705282

African (AFR) AF: 0.0000303 AC: 1 AN: 33000

American (AMR) AF: 0.0000523 AC: 2 AN: 38266

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25398

East Asian (EAS) AF: 0.00 AC: 0 AN: 38188

South Asian (SAS) AF: 0.00 AC: 0 AN: 81476

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49404

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5714

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1094484

Other (OTH) AF: 0.00 AC: 0 AN: 59038

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.35
CardioboostArm	Uncertain	0.44
BayesDel_addAF	Pathogenic	0.29	D
BayesDel_noAF	Pathogenic	0.29
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.68	.;D
Eigen	Uncertain	0.51
Eigen_PC	Uncertain	0.53
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.92	D;D
M_CAP	Pathogenic	0.64	D
MetaRNN	Uncertain	0.72	D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Benign	1.6	.;L
PhyloP100		7.7
PrimateAI	Uncertain	0.68	T
PROVEAN	Benign	-2.3	N;D
REVEL	Pathogenic	0.77
Sift	Uncertain	0.018	D;D
Sift4G	Uncertain	0.021	D;D
Polyphen		0.95	P;D
Vest4		0.51
MutPred		0.34		.;Loss of helix (P = 0.028);
MVP		0.89
MPC		0.69
ClinPred		0.92	D
GERP RS		4.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.51
gMVP		0.67
Mutation Taster		=48/52	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs794728402; hg19: chr7-150644561;