7-150958255-C-A

Variant names:

• chr7-150958255-C-A
• rs899939755
• NM_000238.4:c.720G>T

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PM2 BP4_Strong BP7

The ENST00000262186.10(KCNH2):​c.720G>T​(p.Pro240Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000079 in 1,266,414 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. P240P) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.9e-7 (0 hom.)
• Consequence: KCNH2 ENST00000262186.10 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -3.46
• 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: Likely_benign. The variant received -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.67).
• BP7: Synonymous conserved (PhyloP=-3.46 with no splicing effect.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000262186.10. 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.720G>T	p.Pro240Pro	synonymous	Exon 4 of 15	NP_000229.1
	KCNH2	NM_001406753.1		c.432G>T	p.Pro144Pro	synonymous	Exon 2 of 13	NP_001393682.1
	KCNH2	NM_172056.3		c.720G>T	p.Pro240Pro	synonymous	Exon 4 of 9	NP_742053.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCNH2	ENST00000262186.10	TSL:1 MANE Select	c.720G>T	p.Pro240Pro	synonymous	Exon 4 of 15	ENSP00000262186.5
	KCNH2	ENST00000713710.1		c.720G>T	p.Pro240Pro	synonymous	Exon 4 of 15	ENSP00000519013.1
	KCNH2	ENST00000713701.1		c.420G>T	p.Pro140Pro	synonymous	Exon 3 of 14	ENSP00000519004.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 7.90e-7 AC: 1 AN: 1266414 Hom.: 0 Cov.: 32 AF XY: 0.00000161 AC XY: 1 AN XY: 622252

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 25682

American (AMR) AF: 0.00 AC: 0 AN: 20560

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 20922

East Asian (EAS) AF: 0.00 AC: 0 AN: 27318

South Asian (SAS) AF: 0.00 AC: 0 AN: 63158

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 31544

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3840

European-Non Finnish (NFE) AF: 9.79e-7 AC: 1 AN: 1021374

Other (OTH) AF: 0.00 AC: 0 AN: 52016

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.67
CADD	Benign	0.62
DANN	Benign	0.76
PhyloP100		-3.5

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: rs899939755; hg19: chr7-150655343;