7-150947356-G-A

Variant names:

• chr7-150947356-G-A
• rs1346047270
• NM_000238.4:c.3124C>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_000238.4(KCNH2):​c.3124C>T​(p.Leu1042Leu) variant causes a synonymous change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. L1042L) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: KCNH2 NM_000238.4 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.86
• Publications: 1 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), G2P, Ambry Genetics
• 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: 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 -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.5).

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.3124C>T	p.Leu1042Leu	synonymous	Exon 13 of 15	NP_000229.1	A0A090N8Q0
	KCNH2	NM_001406753.1		c.2836C>T	p.Leu946Leu	synonymous	Exon 11 of 13	NP_001393682.1	Q12809-7
	KCNH2	NM_172057.3		c.2104C>T	p.Leu702Leu	synonymous	Exon 9 of 11	NP_742054.1	Q12809-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCNH2	ENST00000262186.10	TSL:1 MANE Select	c.3124C>T	p.Leu1042Leu	synonymous	Exon 13 of 15	ENSP00000262186.5	Q12809-1
	KCNH2	ENST00000330883.9	TSL:1	c.2104C>T	p.Leu702Leu	synonymous	Exon 9 of 11	ENSP00000328531.4	Q12809-2
	KCNH2	ENST00000713710.1		c.3058C>T	p.Leu1020Leu	synonymous	Exon 13 of 15	ENSP00000519013.1	A0AAQ5BGR0

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.0000139 AC: 2 AN: 144156 AF XY: 0.0000128

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000819

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000144 AC: 2 AN: 1393480 Hom.: 0 Cov.: 35 AF XY: 0.00000145 AC XY: 1 AN XY: 687482

African (AFR) AF: 0.00 AC: 0 AN: 31630

American (AMR) AF: 0.0000560 AC: 2 AN: 35686

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25126

East Asian (EAS) AF: 0.00 AC: 0 AN: 35842

South Asian (SAS) AF: 0.00 AC: 0 AN: 79134

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 43954

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5218

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1079010

Other (OTH) AF: 0.00 AC: 0 AN: 57880

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.50
CADD	Benign	11
DANN	Benign	0.94
PhyloP100		4.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs1346047270; hg19: chr7-150644444;