rs772037564

chr7-150958278-C-Achr7-150958278-C-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Moderate BP6_Very_Strong BS2

The NM_000238.4(KCNH2):c.697G>T(p.Ala233Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000611 in 1,457,400 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A233T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000059 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000061 (2 hom.)
• Consequence: KCNH2 NM_000238.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• 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 Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.103696465).
• BP6: Variant 7-150958278-C-A is Benign according to our data. Variant chr7-150958278-C-A is described in ClinVar as [Likely_benign]. Clinvar id is 527096.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAd at 9 AD,Digenic gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KCNH2	NM_000238.4	c.697G>T	p.Ala233Ser	missense_variant	4/15	ENST00000262186.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KCNH2	ENST00000262186.10	c.697G>T	p.Ala233Ser	missense_variant	4/15	1	NM_000238.4	P1
KCNH2	ENST00000532957.5	n.920G>T		non_coding_transcript_exon_variant	4/9	2
KCNH2	ENST00000684241.1	n.1530G>T		non_coding_transcript_exon_variant	2/13

Frequencies

GnomAD3 genomes AF: 0.0000593 AC: 9 AN: 151862 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00165

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000228 AC: 18 AN: 78984 Hom.: 0 AF XY: 0.000285 AC XY: 13 AN XY: 45542

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00110

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000613 AC: 80 AN: 1305430 Hom.: 2 Cov.: 32 AF XY: 0.0000885 AC XY: 57 AN XY: 643832

Gnomad4 AFR exome AF: 0.0000377

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00100

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.61e-7

Gnomad4 OTH exome AF: 0.000130

GnomAD4 genome AF: 0.0000592 AC: 9 AN: 151970 Hom.: 0 Cov.: 33 AF XY: 0.0000538 AC XY: 4 AN XY: 74302

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00165

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000151

ExAC AF: 0.000101 AC: 9

Asia WGS AF: 0.000300 AC: 1 AN: 3350

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Athena Diagnostics

Dec 22, 2017

- -

Long QT syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Aug 03, 2023

- -

Cardiovascular phenotype Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 10, 2022

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
AlphaMissense	Benign	0.094
CardioboostArm	Benign	0.0044
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.12
Cadd	Benign	19
Dann	Benign	0.94
DEOGEN2	Benign	0.37	T;T
Eigen	Benign	-0.78
Eigen_PC	Benign	-0.80
FATHMM_MKL	Benign	0.34	N
LIST_S2	Benign	0.78	T;T
M_CAP	Pathogenic	0.91	D
MetaRNN	Benign	0.10	T;T
MetaSVM	Uncertain	0.69	D
MutationAssessor	Benign	0.55	N;.
MutationTaster	Benign	0.84	N;N;N
PrimateAI	Pathogenic	0.79	T
PROVEAN	Benign	-0.70	N;.
REVEL	Uncertain	0.32
Sift	Benign	0.18	T;.
Sift4G	Benign	0.42	T;T
Polyphen		0.23	B;.
Vest4		0.14
MutPred		0.16		Gain of phosphorylation at A233 (P = 0.0023);.;
MVP		0.54
MPC		0.93
ClinPred		0.020	T
GERP RS		2.6
Varity_R		0.079
gMVP		0.29

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		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: rs772037564; hg19: chr7-150655366;