ENST00000330883.9:c.81G>C

Variant names:

• chr7-150955423-C-G
• rs990053814
• ENST00000330883.9:c.81G>C

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Moderate BP6_Moderate BP7 BS2

The ENST00000330883.9(KCNH2):​c.81G>C​(p.Val27Val) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000141 in 1,564,634 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: 𝑓 0.000013 (0 hom., cov: 34)
  • Exomes 𝑓: 0.000014 (0 hom.)
• Consequence: KCNH2 ENST00000330883.9 synonymous
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.0810
• 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: Benign. The variant received -9 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.41).
• BP6: Variant 7-150955423-C-G is Benign according to our data. Variant chr7-150955423-C-G is described in ClinVar as Likely_benign. ClinVar VariationId is 527074.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=0.081 with no splicing effect.
• BS2: High AC in GnomAdExome4 at 20 AD gene.

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+1868G>C		intron	N/A	NP_000229.1
	KCNH2	NM_172057.3		c.81G>C	p.Val27Val	synonymous	Exon 1 of 11	NP_742054.1
	KCNH2	NM_001204798.2		c.81G>C	p.Val27Val	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.81G>C	p.Val27Val	synonymous	Exon 1 of 11	ENSP00000328531.4
	KCNH2	ENST00000461280.2	TSL:1	n.399G>C		non_coding_transcript_exon	Exon 1 of 5
	KCNH2	ENST00000262186.10	TSL:1 MANE Select	c.1128+1868G>C		intron	N/A	ENSP00000262186.5

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152262 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000591 AC: 1 AN: 169326 AF XY: 0.0000109

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: 0.0000150

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000142 AC: 20 AN: 1412372 Hom.: 0 Cov.: 31 AF XY: 0.0000115 AC XY: 8 AN XY: 698254

African (AFR) AF: 0.00 AC: 0 AN: 32132

American (AMR) AF: 0.00 AC: 0 AN: 38426

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25300

East Asian (EAS) AF: 0.00 AC: 0 AN: 36654

South Asian (SAS) AF: 0.00 AC: 0 AN: 80106

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48784

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5238

European-Non Finnish (NFE) AF: 0.0000184 AC: 20 AN: 1087316

Other (OTH) AF: 0.00 AC: 0 AN: 58416

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152262 Hom.: 0 Cov.: 34 AF XY: 0.00 AC XY: 0 AN XY: 74382

African (AFR) AF: 0.00 AC: 0 AN: 41476

American (AMR) AF: 0.00 AC: 0 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00 AC: 0 AN: 4838

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10632

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68042

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.0000227

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Long QT syndrome Benign:1

Aug 23, 2017

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	-0.41
CADD	Benign	15
DANN	Benign	0.85
PhyloP100		0.081
PromoterAI		0.042	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.9
Mutation Taster		=99/1	polymorphism

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

Other links and lift over

dbSNP: rs990053814; hg19: chr7-150652511;