rs906562788

Variant names:

• chr7-150948853-C-T
• rs906562788
• NM_000238.4:c.2592+3G>A

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 0P and 3B. BP4_Moderate BS2_Supporting

The NM_000238.4(KCNH2):​c.2592+3G>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000479 in 1,461,760 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000048 (0 hom.)
• Consequence: KCNH2 NM_000238.4 splice_region, intron
• Scores: Splicing: ADA: 0.0005612
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4 B:1
• Conservation: PhyloP100: 0.971

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]

ACMG classification

Verdict is Likely_benign. Variant got -3 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.38).
• BS2: High AC in GnomAdExome4 at 7 AD,Digenic gene. Variant has AC lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNH2	NM_000238.4	c.2592+3G>A		splice_region_variant, intron_variant	Intron 10 of 14	ENST00000262186.10	NP_000229.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KCNH2	ENST00000262186.10	c.2592+3G>A		splice_region_variant, intron_variant	Intron 10 of 14	1	NM_000238.4	ENSP00000262186.5
KCNH2	ENST00000330883.9	c.1572+3G>A		splice_region_variant, intron_variant	Intron 6 of 10	1		ENSP00000328531.4
KCNH2	ENST00000684241.1	n.3425+3G>A		splice_region_variant, intron_variant	Intron 8 of 12

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251180 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135772

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000479 AC: 7 AN: 1461760 Hom.: 0 Cov.: 32 AF XY: 0.00000688 AC XY: 5 AN XY: 727182

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000447

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000450

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Uncertain:1

Oct 20, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: No predicted impact to splicing, only reported in 1 LQT proband -

Short QT syndrome type 1 Uncertain:1

Feb 09, 2021

New York Genome Center

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2592+3G>A variant identified in the KCNH2 gene is a single nucleotide variant at the non-canonical +3 position within intron 10/14. This variant is absent from gnomAD(v3.1) suggesting it is not a common benign variant in the populations represented in that database. In silico algorithm SpliceAI does not suggest this variant to alter splicing (score:0.00). The c.2592+3G>A variant is reported in ClinVar (VarID:402998) as a Variant of Uncertain Significance by two labs and Likely Benign by a single lab with no evidence for that classification. This variant has been reported in the literature in two individuals, one with Left Ventricular Noncompaction [PMID:30471092], and one with suspected Long QT syndrome [PMID:15840476], although the clinical significance was unclear in each case. Given the lack of compelling evidence for its pathogenicity, the c.2592+3G>A variant identified in the KCNH2 gene is reported as a Variant of Uncertain Significance. -

Long QT syndrome Uncertain:1

Apr 16, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change falls in intron 10 of the KCNH2 gene. It does not directly change the encoded amino acid sequence of the KCNH2 protein. It affects a nucleotide within the consensus splice site. This variant is present in population databases (no rsID available, gnomAD 0.003%). This variant has been observed in individual(s) with clinical features of KCNH2-related conditions (PMID: 15840476). ClinVar contains an entry for this variant (Variation ID: 402998). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant is not likely to affect RNA splicing. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Short QT syndrome type 1;C3150943:Long QT syndrome 2 Uncertain:1

Mar 30, 2021

Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

KCNH2 NM_000238.3 exon 10 c.2592+3G>A: This variant has been reported in the literature in 1 individual with a clinical suspicion of Long QT syndrome (Tester 2005 PMID:15840476). This variant is present in 0.002% (1/34562) of Latino alleles in the Genome Aggregation Database (http://gnomad.broadinstitute.org/variant/7-150645941-C-T). This variant is present in ClinVar (Variation ID:402998). Evolutionary conservation and computational predictive tools for this variant are limited or unavailable. This variant is an intronic variant; splice prediction tools suggest that this variant may not affect splicing. However, further studies are needed to understand its impact. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain. -

Cardiac arrhythmia Benign:1

Mar 24, 2019

Color Diagnostics, LLC DBA Color Health

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.38
CADD	Benign	20
DANN	Benign	0.87

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00056
dbscSNV1_RF	Benign	0.0020
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

Publications

LitVar

Other links and lift over

dbSNP: rs906562788; hg19: chr7-150645941;