NM_000238.4:c.685G>T

Variant names:

• chr7-150958290-C-A
• rs730880116
• NM_000238.4:c.685G>T

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.685G>T​(p.Glu229*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. E229E) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: KCNH2 NM_000238.4 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 0.718
• Publications: 5 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 7-150958290-C-A is Pathogenic according to our data. Variant chr7-150958290-C-A is described in ClinVar as Pathogenic. ClinVar VariationId is 180379.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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCNH2	NM_000238.4	MANE Select	c.685G>T	p.Glu229*	stop_gained	Exon 4 of 15	NP_000229.1
	KCNH2	NM_001406753.1		c.397G>T	p.Glu133*	stop_gained	Exon 2 of 13	NP_001393682.1
	KCNH2	NM_172056.3		c.685G>T	p.Glu229*	stop_gained	Exon 4 of 9	NP_742053.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCNH2	ENST00000262186.10	TSL:1 MANE Select	c.685G>T	p.Glu229*	stop_gained	Exon 4 of 15	ENSP00000262186.5
	KCNH2	ENST00000713710.1		c.685G>T	p.Glu229*	stop_gained	Exon 4 of 15	ENSP00000519013.1
	KCNH2	ENST00000713701.1		c.385G>T	p.Glu129*	stop_gained	Exon 3 of 14	ENSP00000519004.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1314242 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 648660

African (AFR) AF: 0.00 AC: 0 AN: 26812

American (AMR) AF: 0.00 AC: 0 AN: 26842

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 22892

East Asian (EAS) AF: 0.00 AC: 0 AN: 28254

South Asian (SAS) AF: 0.00 AC: 0 AN: 72136

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 32888

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4342

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1045802

Other (OTH) AF: 0.00 AC: 0 AN: 54274

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions as Germline

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.52	D
BayesDel_noAF	Pathogenic	0.51
CADD	Pathogenic	36
DANN	Uncertain	1.0
Eigen	Uncertain	0.54
Eigen_PC	Uncertain	0.25
FATHMM_MKL	Uncertain	0.76	D
PhyloP100		0.72
Vest4		0.74
GERP RS		2.6
Mutation Taster		=1/199	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: rs730880116; hg19: chr7-150655378;