rs199473033

Variant names:

• chr7-150945490-C-A
• rs199473033
• NM_000238.4:c.3355G>T

Your query was ambiguous. Multiple possible variants found:

• chr7-150945490-C-A
• chr7-150945490-C-G

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PVS1_Strong PM2 PP5_Moderate

The NM_000238.4(KCNH2):​c.3355G>T​(p.Glu1119*) 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. E1119E) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: KCNH2 NM_000238.4 stop_gained
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 3.51
• 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: Likely_pathogenic. The variant received 8 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 5 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 7-150945490-C-A is Pathogenic according to our data. Variant chr7-150945490-C-A is described in ClinVar as Pathogenic. ClinVar VariationId is 3254535.Status of the report is criteria_provided_single_submitter, 1 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.3355G>T	p.Glu1119*	stop_gained	Exon 15 of 15	NP_000229.1
	KCNH2	NM_001406753.1		c.3067G>T	p.Glu1023*	stop_gained	Exon 13 of 13	NP_001393682.1
	KCNH2	NM_172057.3		c.2335G>T	p.Glu779*	stop_gained	Exon 11 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.3355G>T	p.Glu1119*	stop_gained	Exon 15 of 15	ENSP00000262186.5
	KCNH2	ENST00000330883.9	TSL:1	c.2335G>T	p.Glu779*	stop_gained	Exon 11 of 11	ENSP00000328531.4
	KCNH2	ENST00000713710.1		c.3289G>T	p.Glu1097*	stop_gained	Exon 15 of 15	ENSP00000519013.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1407476 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 694962

African (AFR) AF: 0.00 AC: 0 AN: 31938

American (AMR) AF: 0.00 AC: 0 AN: 36740

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25254

East Asian (EAS) AF: 0.00 AC: 0 AN: 36438

South Asian (SAS) AF: 0.00 AC: 0 AN: 79784

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49298

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5710

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1083944

Other (OTH) AF: 0.00 AC: 0 AN: 58370

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions as Germline

Significance: Pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	Long QT syndrome 2 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.54	D
BayesDel_noAF	Pathogenic	0.54
CADD	Pathogenic	41
DANN	Uncertain	1.0
Eigen	Pathogenic	0.73
Eigen_PC	Uncertain	0.58
FATHMM_MKL	Uncertain	0.87	D
PhyloP100		3.5
Vest4		0.93
GERP RS		5.1
RBP_binding_hub_radar		0.97
RBP_regulation_power_radar		2.7
Mutation Taster		=1/199	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.12		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: rs199473033; hg19: chr7-150642578;