rs41313749

Positions:

• chr7-150945521-TAC-T
• chr7-150945521-TAC-TACAC

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_000238.4(KCNH2):​c.3331-9_3331-8delGT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00287 in 1,557,036 control chromosomes in the GnomAD database, including 125 homozygotes. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.015 (74 hom., cov: 32)
  • Exomes 𝑓: 0.0015 (51 hom.)
• Consequence: KCNH2 NM_000238.4 splice_region, intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 2.08

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -16 ACMG points.

• BP6: Variant 7-150945521-TAC-T is Benign according to our data. Variant chr7-150945521-TAC-T is described in ClinVar as [Likely_benign]. Clinvar id is 200266.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-150945521-TAC-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0517 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KCNH2	NM_000238.4	c.3331-9_3331-8delGT		splice_region_variant, intron_variant		ENST00000262186.10	NP_000229.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KCNH2	ENST00000262186.10	c.3331-9_3331-8delGT		splice_region_variant, intron_variant		1	NM_000238.4	ENSP00000262186.5
KCNH2	ENST00000330883.9	c.2311-9_2311-8delGT		splice_region_variant, intron_variant		1		ENSP00000328531.4
KCNH2	ENST00000684241.1	n.4164-9_4164-8delGT		splice_region_variant, intron_variant

Frequencies

GnomAD3 genomes AF: 0.0154 AC: 2336 AN: 151260 Hom.: 74 Cov.: 32

Gnomad AFR AF: 0.0537

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00591

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000209

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00318

Gnomad NFE AF: 0.000177

Gnomad OTH AF: 0.0124

GnomAD3 exomes AF: 0.00367 AC: 593 AN: 161778 Hom.: 20 AF XY: 0.00260 AC XY: 223 AN XY: 85904

Gnomad AFR exome AF: 0.0549

Gnomad AMR exome AF: 0.00295

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000432

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000159

Gnomad OTH exome AF: 0.00175

GnomAD4 exome AF: 0.00152 AC: 2139 AN: 1405658 Hom.: 51 AF XY: 0.00131 AC XY: 912 AN XY: 693924

Gnomad4 AFR exome AF: 0.0552

Gnomad4 AMR exome AF: 0.00294

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000113

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000563

Gnomad4 OTH exome AF: 0.00326

GnomAD4 genome AF: 0.0154 AC: 2334 AN: 151378 Hom.: 74 Cov.: 32 AF XY: 0.0150 AC XY: 1110 AN XY: 73908

Gnomad4 AFR AF: 0.0536

Gnomad4 AMR AF: 0.00591

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000177

Gnomad4 OTH AF: 0.0123

Alfa AF: 0.00764 Hom.: 2

Bravo AF: 0.0174

Asia WGS AF: 0.00202 AC: 7 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 19, 2013	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Sep 03, 2019	Variant summary: KCNH2 c.3331-9_3331-8delGT alters a nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. 5/5 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.0037 in 161778 control chromosomes, predominantly at a frequency of 0.055 within the African or African-American subpopulation in the gnomAD database, including 19 homozygotes. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 550 fold of the estimated maximal expected allele frequency for a pathogenic variant in KCNH2 causing Arrhythmia phenotype (0.0001), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African or African-American origin. Four ClinVar submitters (evaluation after 2014) cite the variant as benign (3x) and once as likely benign. Based on the evidence outlined above, the variant was classified as benign. -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jul 05, 2017	- -

Long QT syndrome Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 14, 2016	- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Jun 30, 2022

- -

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

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Feb 15, 2022

- -

Cardiac arrhythmia Benign:1

Benign, criteria provided, single submitter

clinical testing

Color Diagnostics, LLC DBA Color Health

Mar 15, 2018

- -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs41313749; hg19: chr7-150642609;