7-150947306-C-T

Variant names:

• chr7-150947306-C-T
• rs3815459
• NM_000238.4:c.3152+22G>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.3152+22G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.252 in 1,529,804 control chromosomes in the GnomAD database, including 56,789 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 0.29 (7042 hom., cov: 32)
  • Exomes 𝑓: 0.25 (49747 hom.)
• Consequence: KCNH2 NM_000238.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.37
• Publications: 25 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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.687 is higher than 0.05.

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.3152+22G>A		intron	N/A	NP_000229.1	A0A090N8Q0
	KCNH2	NM_001406753.1		c.2864+22G>A		intron	N/A	NP_001393682.1	Q12809-7
	KCNH2	NM_172057.3		c.2132+22G>A		intron	N/A	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.3152+22G>A		intron	N/A	ENSP00000262186.5	Q12809-1
	KCNH2	ENST00000330883.9	TSL:1	c.2132+22G>A		intron	N/A	ENSP00000328531.4	Q12809-2
	KCNH2	ENST00000713710.1		c.3086+22G>A		intron	N/A	ENSP00000519013.1	A0AAQ5BGR0

Frequencies

GnomAD3 genomes AF: 0.286 AC: 43423 AN: 151842 Hom.: 7026 Cov.: 32

Gnomad AFR AF: 0.314

Gnomad AMI AF: 0.274

Gnomad AMR AF: 0.342

Gnomad ASJ AF: 0.339

Gnomad EAS AF: 0.705

Gnomad SAS AF: 0.357

Gnomad FIN AF: 0.308

Gnomad MID AF: 0.275

Gnomad NFE AF: 0.214

Gnomad OTH AF: 0.278

GnomAD2 exomes AF: 0.335 AC: 45290 AN: 135222 AF XY: 0.331

Gnomad AFR exome AF: 0.313

Gnomad AMR exome AF: 0.416

Gnomad ASJ exome AF: 0.338

Gnomad EAS exome AF: 0.708

Gnomad FIN exome AF: 0.309

Gnomad NFE exome AF: 0.220

Gnomad OTH exome AF: 0.305

GnomAD4 exome AF: 0.248 AC: 341706 AN: 1377844 Hom.: 49747 Cov.: 32 AF XY: 0.252 AC XY: 171253 AN XY: 679968

African (AFR) AF: 0.320 AC: 10069 AN: 31432

American (AMR) AF: 0.405 AC: 14372 AN: 35486

Ashkenazi Jewish (ASJ) AF: 0.331 AC: 8245 AN: 24922

East Asian (EAS) AF: 0.754 AC: 26902 AN: 35696

South Asian (SAS) AF: 0.362 AC: 28462 AN: 78696

European-Finnish (FIN) AF: 0.289 AC: 10739 AN: 37152

Middle Eastern (MID) AF: 0.299 AC: 1440 AN: 4822

European-Non Finnish (NFE) AF: 0.210 AC: 225626 AN: 1072120

Other (OTH) AF: 0.276 AC: 15851 AN: 57518

GnomAD4 genome AF: 0.286 AC: 43467 AN: 151960 Hom.: 7042 Cov.: 32 AF XY: 0.295 AC XY: 21883 AN XY: 74280

African (AFR) AF: 0.314 AC: 13006 AN: 41446

American (AMR) AF: 0.342 AC: 5233 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.339 AC: 1178 AN: 3470

East Asian (EAS) AF: 0.706 AC: 3612 AN: 5118

South Asian (SAS) AF: 0.358 AC: 1724 AN: 4820

European-Finnish (FIN) AF: 0.308 AC: 3259 AN: 10580

Middle Eastern (MID) AF: 0.265 AC: 78 AN: 294

European-Non Finnish (NFE) AF: 0.214 AC: 14527 AN: 67926

Other (OTH) AF: 0.285 AC: 601 AN: 2110

Alfa AF: 0.230 Hom.: 5668

Bravo AF: 0.294

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	0.40
DANN	Benign	0.90
PhyloP100		-1.4
Mutation Taster		=100/0	polymorphism (auto)

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: rs3815459; hg19: chr7-150644394; COSMIC: COSV51211598; COSMIC: COSV51211598;