rs1554426874

Variant names:

• chr7-150955420-G-A
• rs1554426874
• ENST00000330883.9:c.84C>T

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PM2 BP4_Moderate BP6_Moderate BP7

The ENST00000330883.9(KCNH2):​c.84C>T​(p.Arg28Arg) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000708 in 1,412,030 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 7.1e-7 (0 hom.)
• Consequence: KCNH2 ENST00000330883.9 synonymous
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.52
• 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_benign. The variant received -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.29).
• BP6: Variant 7-150955420-G-A is Benign according to our data. Variant chr7-150955420-G-A is described in ClinVar as Likely_benign. ClinVar VariationId is 456880.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=1.52 with no splicing effect.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000330883.9. 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.1128+1871C>T		intron	N/A	NP_000229.1
	KCNH2	NM_172057.3		c.84C>T	p.Arg28Arg	synonymous	Exon 1 of 11	NP_742054.1
	KCNH2	NM_001204798.2		c.84C>T	p.Arg28Arg	synonymous	Exon 1 of 5	NP_001191727.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCNH2	ENST00000330883.9	TSL:1	c.84C>T	p.Arg28Arg	synonymous	Exon 1 of 11	ENSP00000328531.4
	KCNH2	ENST00000461280.2	TSL:1	n.402C>T		non_coding_transcript_exon	Exon 1 of 5
	KCNH2	ENST00000262186.10	TSL:1 MANE Select	c.1128+1871C>T		intron	N/A	ENSP00000262186.5

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome AF: 7.08e-7 AC: 1 AN: 1412030 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 698038

African (AFR) AF: 0.00 AC: 0 AN: 32116

American (AMR) AF: 0.00 AC: 0 AN: 38330

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25298

East Asian (EAS) AF: 0.00 AC: 0 AN: 36656

South Asian (SAS) AF: 0.00 AC: 0 AN: 80064

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48786

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5288

European-Non Finnish (NFE) AF: 9.20e-7 AC: 1 AN: 1087086

Other (OTH) AF: 0.00 AC: 0 AN: 58406

GnomAD4 genome Cov.: 34

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Long QT syndrome Benign:1

Dec 31, 2019

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.29
CADD	Benign	18
DANN	Benign	0.95
PhyloP100		1.5
PromoterAI		0.048	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.9

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: rs1554426874; hg19: chr7-150652508;