NM_000238.4:c.76+496G>A

Variant names:

• chr7-150977342-C-T
• rs1036145
• NM_000238.4:c.76+496G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000238.4(KCNH2):​c.76+496G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.265 in 152,052 control chromosomes in the GnomAD database, including 6,070 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.26 (6070 hom., cov: 31)
• Consequence: KCNH2 NM_000238.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.03
• Publications: 18 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

LOC124901776 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.341 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNH2	NM_000238.4	c.76+496G>A		intron_variant	Intron 1 of 14	ENST00000262186.10	NP_000229.1
LOC124901776	XR_007060592.1	n.832C>T		non_coding_transcript_exon_variant	Exon 3 of 3
KCNH2	NM_172056.3	c.76+496G>A		intron_variant	Intron 1 of 8		NP_742053.1
KCNH2	NR_176254.1	n.484+496G>A		intron_variant	Intron 1 of 14

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KCNH2	ENST00000262186.10	c.76+496G>A		intron_variant	Intron 1 of 14	1	NM_000238.4	ENSP00000262186.5
KCNH2	ENST00000713710.1	c.76+496G>A		intron_variant	Intron 1 of 14			ENSP00000519013.1
KCNH2	ENST00000532957.5	n.299+496G>A		intron_variant	Intron 1 of 8	2

Frequencies

GnomAD3 genomes AF: 0.265 AC: 40207 AN: 151934 Hom.: 6070 Cov.: 31

Gnomad AFR AF: 0.127

Gnomad AMI AF: 0.417

Gnomad AMR AF: 0.283

Gnomad ASJ AF: 0.307

Gnomad EAS AF: 0.134

Gnomad SAS AF: 0.304

Gnomad FIN AF: 0.280

Gnomad MID AF: 0.255

Gnomad NFE AF: 0.345

Gnomad OTH AF: 0.262

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.265 AC: 40221 AN: 152052 Hom.: 6070 Cov.: 31 AF XY: 0.260 AC XY: 19306 AN XY: 74340

African (AFR) AF: 0.127 AC: 5287 AN: 41478

American (AMR) AF: 0.283 AC: 4327 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.307 AC: 1065 AN: 3472

East Asian (EAS) AF: 0.135 AC: 698 AN: 5186

South Asian (SAS) AF: 0.304 AC: 1465 AN: 4818

European-Finnish (FIN) AF: 0.280 AC: 2956 AN: 10568

Middle Eastern (MID) AF: 0.250 AC: 73 AN: 292

European-Non Finnish (NFE) AF: 0.345 AC: 23429 AN: 67950

Other (OTH) AF: 0.257 AC: 542 AN: 2108

Alfa AF: 0.303 Hom.: 5035

Bravo AF: 0.257

Asia WGS AF: 0.216 AC: 753 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	4.2
DANN	Benign	0.81
PhyloP100		-1.0
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1036145; hg19: chr7-150674430; COSMIC: COSV51192557;