rs757132095

chr7-150959693-G-A

Variant summary

Our verdict is Benign. Variant got -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BP7 BS2

The NM_000238.4(KCNH2):c.351C>T(p.Asn117=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000335 in 1,613,996 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000035 (0 hom.)
• Consequence: KCNH2 NM_000238.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.381

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 -17 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.49).
• BP6: Variant 7-150959693-G-A is Benign according to our data. Variant chr7-150959693-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 413344.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-150959693-G-A is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-0.381 with no splicing effect.
• BS2: High AC in GnomAdExome at 8 AD,Digenic gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KCNH2	NM_000238.4	c.351C>T	p.Asn117=	synonymous_variant	3/15	ENST00000262186.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KCNH2	ENST00000262186.10	c.351C>T	p.Asn117=	synonymous_variant	3/15	1	NM_000238.4	P1
KCNH2	ENST00000532957.5	n.574C>T		non_coding_transcript_exon_variant	3/9	2
KCNH2	ENST00000684241.1	n.1184C>T		non_coding_transcript_exon_variant	1/13

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152112 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000318 AC: 8 AN: 251422 Hom.: 0 AF XY: 0.0000368 AC XY: 5 AN XY: 135908

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000109

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000440

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000349 AC: 51 AN: 1461884 Hom.: 0 Cov.: 32 AF XY: 0.0000413 AC XY: 30 AN XY: 727244

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000327

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000288

Gnomad4 OTH exome AF: 0.0000662

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152112 Hom.: 0 Cov.: 33 AF XY: 0.0000269 AC XY: 2 AN XY: 74290

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000565 Hom.: 0

Bravo AF: 0.0000264

EpiCase AF: 0.000109

EpiControl AF: 0.00

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Long QT syndrome Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Invitae	Sep 04, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Oct 27, 2023	- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Mar 03, 2015

- -

Cardiovascular phenotype Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 29, 2021

This alteration is classified as likely 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. -

Cardiac arrhythmia Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Color Diagnostics, LLC DBA Color Health

Mar 16, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.49
Cadd	Benign	6.2
Dann	Benign	0.87

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs757132095; hg19: chr7-150656781;