7-150947419-TG-TGG

Position:

• chr7-150947419-TG-TGG

Variant summary

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

The NM_000238.4(KCNH2):​c.3060_3061insC​(p.Ser1021GlnfsTer98) 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 Likely pathogenic (★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 33)
• Consequence: KCNH2 NM_000238.4 frameshift
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: -0.174

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 7-150947419-T-TG is Pathogenic according to our data. Variant chr7-150947419-T-TG is described in ClinVar as [Likely_pathogenic]. Clinvar id is 423015.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.3060_3061insC	p.Ser1021GlnfsTer98	frameshift_variant	13/15	ENST00000262186.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KCNH2	ENST00000262186.10	c.3060_3061insC	p.Ser1021GlnfsTer98	frameshift_variant	13/15	1	NM_000238.4	P1
KCNH2	ENST00000330883.9	c.2040_2041insC	p.Ser681GlnfsTer98	frameshift_variant	9/11	1
KCNH2	ENST00000684241.1	n.3893_3894insC		non_coding_transcript_exon_variant	11/13

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 37

GnomAD4 genome Cov.: 33

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Oct 26, 2017

The c.3060dupC variant was identified in 5 relatives from a family referred for LQTS genetic testing (Itoh et al., 2015). However, detailed clinical information was not provided. This variant causes a shift in reading frame starting at codon serine 1021, changing it to a glutamine, and creating a premature stop codon at position 98 of the new reading frame, denoted p.Ser1021GlnfsX98. Because the new termination codon is located in the last exon, nonsense-mediated mRNA decay is not expected. This variant is expected to result in an abnormal, truncated protein product, in which the last 139 amino acids are replaced by 97 different amino acids. It is not known whether this abnormal protein is stable or, if stable, what the precise effect is of this variant. However, multiple other downstream frameshift variants in the KCNH2 gene have been reported in Human Gene Mutation Database in association with LQTS (Stenson et al., 2014), suggesting loss of function as a mechanism of disease. Lastly, data from control individuals in publicly available databases is not available to assess the frequency of c.3060dupC in the general population. -

Computational scores

Source: dbNSFP v4.3

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

Publications

LitVar

Other links and lift over

dbSNP: rs864622174; hg19: chr7-150644507;