7-150948437-G-T

Variant names:

• chr7-150948437-G-T
• rs372023163
• NM_000238.4:c.2692+7C>A

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_000238.4(KCNH2):​c.2692+7C>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 0)
  • Exomes 𝑓: 0.0000038 (0 hom.)
• Consequence: KCNH2 NM_000238.4 splice_region, intron
• Scores: Splicing: ADA: 0.0004497
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.817
• 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 -4 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.72).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNH2	NM_000238.4	c.2692+7C>A		splice_region_variant, intron_variant	Intron 11 of 14	ENST00000262186.10	NP_000229.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KCNH2	ENST00000262186.10	c.2692+7C>A		splice_region_variant, intron_variant	Intron 11 of 14	1	NM_000238.4	ENSP00000262186.5

Frequencies

GnomAD3 genomes Cov.: 0

GnomAD4 exome AF: 0.00000382 AC: 2 AN: 523180 Hom.: 0 Cov.: 16 AF XY: 0.00000726 AC XY: 2 AN XY: 275554

⚠️ 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: 7144

American (AMR) AF: 0.00 AC: 0 AN: 23642

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 12200

East Asian (EAS) AF: 0.00 AC: 0 AN: 10566

South Asian (SAS) AF: 0.00 AC: 0 AN: 46484

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 20478

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3072

European-Non Finnish (NFE) AF: 0.00000265 AC: 1 AN: 377676

Other (OTH) AF: 0.0000456 AC: 1 AN: 21918

⚠️ 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.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.72
CADD	Benign	1.3
DANN	Benign	0.96
PhyloP100		-0.82

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00045
dbscSNV1_RF	Benign	0.014
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: rs372023163; hg19: chr7-150645525;