rs1554424062

chr7-150947373-C-CCCCGGGG

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_000238.4(KCNH2):c.3106_3107insCCCCGGG(p.Gly1036AlafsTer85) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★). Synonymous variant affecting the same amino acid position (i.e. G1036G) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 33)
• Consequence: KCNH2 NM_000238.4 frameshift
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: -0.189

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]

ACMG classification

Verdict is Pathogenic. Variant got 12 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 7-150947373-C-CCCCGGGG is Pathogenic according to our data. Variant chr7-150947373-C-CCCCGGGG is described in ClinVar as [Pathogenic]. Clinvar id is 456921.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KCNH2	NM_000238.4	c.3106_3107insCCCCGGG	p.Gly1036AlafsTer85	frameshift_variant	13/15	ENST00000262186.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KCNH2	ENST00000262186.10	c.3106_3107insCCCCGGG	p.Gly1036AlafsTer85	frameshift_variant	13/15	1	NM_000238.4	P1
KCNH2	ENST00000330883.9	c.2086_2087insCCCCGGG	p.Gly696AlafsTer85	frameshift_variant	9/11	1
KCNH2	ENST00000684241.1	n.3939_3940insCCCCGGG		non_coding_transcript_exon_variant	11/13

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Long QT syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Mar 13, 2020

For these reasons, this variant has been classified as Pathogenic. This variant disrupts the C-terminus of the KCNH2 protein. Other variant(s) that disrupt this region (p.Glu1119*) have been determined to be pathogenic (PMID: 27920829, Invitae). This suggests that variants that disrupt this region of the protein are likely to be causative of disease. This variant has not been reported in the literature in individuals with KCNH2-related conditions. ClinVar contains an entry for this variant (Variation ID: 456921). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate insufficient coverage at this position in the ExAC database. This sequence change results in a premature translational stop signal in the KCNH2 gene (p.Gly1036Alafs*85). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 124 amino acids of the KCNH2 protein. -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs1554424062; hg19: chr7-150644461;