rs989191027

chr7-150958293-C-Gchr7-150958293-C-T

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_000238.4(KCNH2):c.682G>C(p.Ala228Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000545 in 1,466,674 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A228V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000040 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000015 (0 hom.)
• Consequence: KCNH2 NM_000238.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 0.0270

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 -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.23228768).
• BS2: High AC in GnomAd at 6 AD,Digenic gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KCNH2	NM_000238.4	c.682G>C	p.Ala228Pro	missense_variant	4/15	ENST00000262186.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KCNH2	ENST00000262186.10	c.682G>C	p.Ala228Pro	missense_variant	4/15	1	NM_000238.4	P1
KCNH2	ENST00000532957.5	n.905G>C		non_coding_transcript_exon_variant	4/9	2
KCNH2	ENST00000684241.1	n.1515G>C		non_coding_transcript_exon_variant	2/13

Frequencies

GnomAD3 genomes AF: 0.0000395 AC: 6 AN: 151852 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000121

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: 0.00

Gnomad OTH AF: 0.000479

GnomAD4 exome AF: 0.00000152 AC: 2 AN: 1314822 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 649004

Gnomad4 AFR exome AF: 0.0000745

Gnomad4 AMR exome AF: 0.00

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000395 AC: 6 AN: 151852 Hom.: 0 Cov.: 33 AF XY: 0.0000539 AC XY: 4 AN XY: 74162

Gnomad4 AFR AF: 0.000121

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: 0.00

Gnomad4 OTH AF: 0.000479

Bravo AF: 0.0000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Long QT syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Dec 06, 2022

Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. 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. ClinVar contains an entry for this variant (Variation ID: 526974). This variant has not been reported in the literature in individuals affected with KCNH2-related conditions. This variant is present in population databases (no rsID available, gnomAD 0.02%). This sequence change replaces alanine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 228 of the KCNH2 protein (p.Ala228Pro). -

Cardiovascular phenotype Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 08, 2023

The p.A228P variant (also known as c.682G>C), located in coding exon 4 of the KCNH2 gene, results from a G to C substitution at nucleotide position 682. The alanine at codon 228 is replaced by proline, an amino acid with highly similar properties. This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

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

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Sep 20, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.069
CardioboostArm	Benign	0.00018
BayesDel_addAF	Uncertain	0.045	T
BayesDel_noAF	Benign	-0.17
Cadd	Benign	13
Dann	Benign	0.97
DEOGEN2	Benign	0.34	T;T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.12	N
LIST_S2	Benign	0.64	T;T
M_CAP	Pathogenic	0.94	D
MetaRNN	Benign	0.23	T;T
MetaSVM	Uncertain	0.30	D
MutationAssessor	Benign	0.69	N;.
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Pathogenic	0.86	D
PROVEAN	Benign	-0.54	N;.
REVEL	Uncertain	0.37
Sift	Benign	0.11	T;.
Sift4G	Benign	0.29	T;T
Polyphen		0.0	B;.
Vest4		0.12
MVP		0.74
MPC		1.3
ClinPred		0.051	T
GERP RS		0.59
Varity_R		0.089
gMVP		0.51

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs989191027; hg19: chr7-150655381;