7-150945350-C-T

Variant names:

• chr7-150945350-C-T
• rs41313746
• NM_000238.4:c.*15G>A

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BS1 BS2

The NM_000238.4(KCNH2):​c.*15G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00211 in 1,582,518 control chromosomes in the GnomAD database, including 67 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.011 (33 hom., cov: 33)
  • Exomes 𝑓: 0.0011 (34 hom.)
• Consequence: KCNH2 NM_000238.4 3_prime_UTR
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.822

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 Benign. Variant got -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.39).
• BP6: Variant 7-150945350-C-T is Benign according to our data. Variant chr7-150945350-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 359300.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-150945350-C-T is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0114 (1735/152284) while in subpopulation AFR AF= 0.0395 (1640/41564). AF 95% confidence interval is 0.0379. There are 33 homozygotes in gnomad4. There are 820 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 1735 AD,Digenic gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNH2	NM_000238.4	c.*15G>A		3_prime_UTR_variant	Exon 15 of 15	ENST00000262186.10	NP_000229.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KCNH2	ENST00000262186	c.*15G>A		3_prime_UTR_variant	Exon 15 of 15	1	NM_000238.4	ENSP00000262186.5
KCNH2	ENST00000330883	c.*15G>A		3_prime_UTR_variant	Exon 11 of 11	1		ENSP00000328531.4
KCNH2	ENST00000684241.1	n.4328G>A		non_coding_transcript_exon_variant	Exon 13 of 13

Frequencies

GnomAD3 genomes AF: 0.0114 AC: 1736 AN: 152168 Hom.: 33 Cov.: 33

Gnomad AFR AF: 0.0396

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00425

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000132

Gnomad OTH AF: 0.00955

GnomAD3 exomes AF: 0.00262 AC: 522 AN: 199372 Hom.: 13 AF XY: 0.00195 AC XY: 211 AN XY: 108244

Gnomad AFR exome AF: 0.0404

Gnomad AMR exome AF: 0.00205

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000390

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000117

Gnomad OTH exome AF: 0.000390

GnomAD4 exome AF: 0.00112 AC: 1597 AN: 1430234 Hom.: 34 Cov.: 31 AF XY: 0.000949 AC XY: 672 AN XY: 708458

Gnomad4 AFR exome AF: 0.0404

Gnomad4 AMR exome AF: 0.00200

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000856

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000419

Gnomad4 OTH exome AF: 0.00225

GnomAD4 genome AF: 0.0114 AC: 1735 AN: 152284 Hom.: 33 Cov.: 33 AF XY: 0.0110 AC XY: 820 AN XY: 74458

Gnomad4 AFR AF: 0.0395

Gnomad4 AMR AF: 0.00425

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000132

Gnomad4 OTH AF: 0.00945

Alfa AF: 0.00489 Hom.: 2

Bravo AF: 0.0126

Asia WGS AF: 0.00144 AC: 5 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jun 30, 2022

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Long QT syndrome 2 Benign:1

Feb 06, 2018

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

not specified Benign:1

Sep 03, 2019

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: KCNH2 c.*15G>A is located in the untranslated mRNA region downstream of the termination codon. 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 0.0026 in 199372 control chromosomes in the gnomAD database, including 13 homozygotes. The observed variant frequency is approximately 26 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 benign. To our knowledge, no occurrence of c.*15G>A in individuals affected with Arrhythmia and no experimental evidence demonstrating its impact on protein function have been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as likely benign. Based on the evidence outlined above, the variant was classified as benign. -

Cardiovascular phenotype Benign:1

Dec 18, 2014

Ambry Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.39
CADD	Benign	13
DANN	Benign	0.93

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

Publications

LitVar

Other links and lift over

dbSNP: rs41313746; hg19: chr7-150642438;