rs864622174

Variant names:

• chr7-150947419-TG-T
• rs864622174
• NM_000238.4:c.3060delC

Your query was ambiguous. Multiple possible variants found:

• chr7-150947419-TG-T
• chr7-150947419-TG-TGG

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_000238.4(KCNH2):​c.3060delC​(p.Ser1021AlafsTer36) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000151 in 1,325,136 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000015 (0 hom.)
• Consequence: KCNH2 NM_000238.4 frameshift
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: -0.174
• Publications: 3 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: Pathogenic. The variant received 18 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-TG-T is Pathogenic according to our data. Variant chr7-150947419-TG-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 219597.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000238.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCNH2	NM_000238.4	MANE Select	c.3060delC	p.Ser1021AlafsTer36	frameshift	Exon 13 of 15	NP_000229.1
	KCNH2	NM_001406753.1		c.2772delC	p.Ser925AlafsTer36	frameshift	Exon 11 of 13	NP_001393682.1
	KCNH2	NM_172057.3		c.2040delC	p.Ser681AlafsTer36	frameshift	Exon 9 of 11	NP_742054.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCNH2	ENST00000262186.10	TSL:1 MANE Select	c.3060delC	p.Ser1021AlafsTer36	frameshift	Exon 13 of 15	ENSP00000262186.5
	KCNH2	ENST00000330883.9	TSL:1	c.2040delC	p.Ser681AlafsTer36	frameshift	Exon 9 of 11	ENSP00000328531.4
	KCNH2	ENST00000713710.1		c.2994delC	p.Ser999AlafsTer36	frameshift	Exon 13 of 15	ENSP00000519013.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00 AC: 0 AN: 152342 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

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: 0.00000151 AC: 2 AN: 1325136 Hom.: 0 Cov.: 37 AF XY: 0.00000152 AC XY: 1 AN XY: 656690

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 30344

American (AMR) AF: 0.00 AC: 0 AN: 35288

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24148

East Asian (EAS) AF: 0.00 AC: 0 AN: 32606

South Asian (SAS) AF: 0.00 AC: 0 AN: 78066

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 46370

Middle Eastern (MID) AF: 0.000191 AC: 1 AN: 5248

European-Non Finnish (NFE) AF: 9.82e-7 AC: 1 AN: 1018006

Other (OTH) AF: 0.00 AC: 0 AN: 55060

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.00666416), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions as Germline

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
2	-	-	not provided (2)
1	-	-	Long QT syndrome (1)
1	-	-	Long QT syndrome 2 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.17
Mutation Taster		=0/200	disease causing (ClinVar)

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: rs864622174; hg19: chr7-150644507;