rs1167016668

Variant names:

• chr7-150955442-C-G
• rs1167016668
• ENST00000330883.9:c.62G>C

Your query was ambiguous. Multiple possible variants found:

• chr7-150955442-C-G
• chr7-150955442-C-T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 3P and 2B. PM2 PP2 BP4_Moderate

The ENST00000330883.9(KCNH2):​c.62G>C​(p.Gly21Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000141 in 1,413,506 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 11/18 in silico tools predict a benign outcome for this variant. 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. G21D) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: KCNH2 ENST00000330883.9 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.74
• 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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• 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: 2.8194 (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=0.103153676).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNH2	NM_000238.4	c.1128+1849G>C		intron_variant	Intron 5 of 14	ENST00000262186.10	NP_000229.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KCNH2	ENST00000262186.10	c.1128+1849G>C		intron_variant	Intron 5 of 14	1	NM_000238.4	ENSP00000262186.5

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome AF: 0.00000141 AC: 2 AN: 1413506 Hom.: 0 Cov.: 31 AF XY: 0.00000143 AC XY: 1 AN XY: 698904

African (AFR) AF: 0.00 AC: 0 AN: 32140

American (AMR) AF: 0.00 AC: 0 AN: 38666

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25294

East Asian (EAS) AF: 0.00 AC: 0 AN: 36684

South Asian (SAS) AF: 0.00 AC: 0 AN: 80130

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48852

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5116

European-Non Finnish (NFE) AF: 0.00000184 AC: 2 AN: 1088192

Other (OTH) AF: 0.00 AC: 0 AN: 58432

GnomAD4 genome Cov.: 34

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.098
BayesDel_addAF	Uncertain	0.016	T
BayesDel_noAF	Benign	-0.21
CADD	Benign	20
DANN	Benign	0.96
Eigen	Benign	-0.43
Eigen_PC	Benign	-0.20
FATHMM_MKL	Benign	0.22	N
LIST_S2	Benign	0.59	T
M_CAP	Uncertain	0.18	D
MetaRNN	Benign	0.10	T
MetaSVM	Uncertain	0.20	D
PhyloP100		1.7
PROVEAN	Benign	-0.45	N
REVEL	Uncertain	0.31
Sift	Benign	0.59	T
Sift4G	Benign	0.45	T
Polyphen		0.0010	B
Vest4		0.10
MutPred		0.30		Loss of loop (P = 9e-04);
MVP		0.43
ClinPred		0.28	T
GERP RS		4.1
PromoterAI		-0.035	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=85/15	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: rs1167016668; hg19: chr7-150652530;