ENST00000330883.9:c.96C>T

Variant names:

• chr7-150955408-G-A
• rs199698029
• ENST00000330883.9:c.96C>T
• KCNH2 p.Leu32Leu

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.96C>T​(p.Leu32Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000416 in 1,561,218 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★). Synonymous variant affecting the same amino acid position (i.e. L32L) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000066 (0 hom., cov: 34)
  • Exomes 𝑓: 0.000039 (1 hom.)
• Consequence: KCNH2 ENST00000330883.9 synonymous
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.433
• 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: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae)
• short QT syndrome

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
• short QT syndrome type 1

  Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P
• 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=-0.39).
• BP6: Variant 7-150955408-G-A is Benign according to our data. Variant chr7-150955408-G-A is described in ClinVar as Likely_benign. ClinVar VariationId is 701128.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=-0.433 with no splicing effect.
• BS2: High AC in GnomAd4 at 10 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCNH2	NM_000238.4	MANE Select	c.1128+1883C>T		intron	N/A	NP_000229.1	A0A090N8Q0
	KCNH2	NM_172057.3		c.96C>T	p.Leu32Leu	synonymous	Exon 1 of 11	NP_742054.1	Q12809-2
	KCNH2	NM_001204798.2		c.96C>T	p.Leu32Leu	synonymous	Exon 1 of 5	NP_001191727.1	Q12809-6

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCNH2	ENST00000330883.9	TSL:1	c.96C>T	p.Leu32Leu	synonymous	Exon 1 of 11	ENSP00000328531.4	Q12809-2
	KCNH2	ENST00000262186.10	TSL:1 MANE Select	c.1128+1883C>T		intron	N/A	ENSP00000262186.5	Q12809-1
	KCNH2	ENST00000461280.2	TSL:1	n.414C>T		non_coding_transcript_exon	Exon 1 of 5

Frequencies

GnomAD3 genomes AF: 0.0000657 AC: 10 AN: 152244 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.0000482

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000392

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000386

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000968 AC: 16 AN: 165228 AF XY: 0.000123

Gnomad AFR exome AF: 0.000110

Gnomad AMR exome AF: 0.0000748

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000479

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000155

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000390 AC: 55 AN: 1408856 Hom.: 1 Cov.: 31 AF XY: 0.0000388 AC XY: 27 AN XY: 696170

African (AFR) AF: 0.000125 AC: 4 AN: 32012

American (AMR) AF: 0.0000530 AC: 2 AN: 37738

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25256

East Asian (EAS) AF: 0.000494 AC: 18 AN: 36468

South Asian (SAS) AF: 0.000226 AC: 18 AN: 79804

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48642

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5418

European-Non Finnish (NFE) AF: 0.0000111 AC: 12 AN: 1085192

Other (OTH) AF: 0.0000171 AC: 1 AN: 58326

GnomAD4 genome AF: 0.0000656 AC: 10 AN: 152362 Hom.: 0 Cov.: 34 AF XY: 0.0000671 AC XY: 5 AN XY: 74494

African (AFR) AF: 0.0000481 AC: 2 AN: 41598

American (AMR) AF: 0.000392 AC: 6 AN: 15312

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

East Asian (EAS) AF: 0.000387 AC: 2 AN: 5174

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68032

Other (OTH) AF: 0.00 AC: 0 AN: 2116

Alfa AF: 0.000171 Hom.: 0

Bravo AF: 0.0000529

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.39
CADD	Benign	16
DANN	Benign	0.95
PhyloP100		-0.43
PromoterAI		0.088	Neutral
Mutation Taster		=99/1	polymorphism

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs199698029;

hg19: chr7-150652496;