rs199472846

chr7-150974849-C-Gchr7-150974849-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1 PM2 PM5 PP3

The NM_000238.4(KCNH2):c.169G>C(p.Ala57Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic 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. A57V) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 34)
• Consequence: KCNH2 NM_000238.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1 O:1
• Conservation: PhyloP100: 1.89

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_pathogenic. Variant got 7 ACMG points.

• PM1: In a hotspot region, there are 8 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 16 uncertain in NM_000238.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr7-150974848-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 200775.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, Uncertain_significance=1}.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.765

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KCNH2	NM_000238.4	c.169G>C	p.Ala57Pro	missense_variant	2/15	ENST00000262186.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KCNH2	ENST00000262186.10	c.169G>C	p.Ala57Pro	missense_variant	2/15	1	NM_000238.4	P1
KCNH2	ENST00000532957.5	n.392G>C		non_coding_transcript_exon_variant	2/9	2

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 34

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1 Other:1

Revision: criteria provided, single submitter

Submissions by phenotype

Long QT syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Jul 22, 2019

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. This variant has been reported to affect KCNH2 protein function (PMID: 29725305). This variant has been observed in an individual referred for long QT genetic testing (PMID: 19716085). ClinVar contains an entry for this variant (Variation ID: 67240). This variant is not present in population databases (ExAC no frequency). This sequence change replaces alanine with proline at codon 57 of the KCNH2 protein (p.Ala57Pro). The alanine residue is weakly conserved and there is a small physicochemical difference between alanine and proline. -

Congenital long QT syndrome Other:1

not provided, no classification provided

literature only

Cardiovascular Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust

-

This variant has been reported as associated with Long QT syndrome in the following publications (PMID:19716085). This is a literature report, and does not necessarily reflect the clinical interpretation of the Imperial College / Royal Brompton Cardiovascular Genetics laboratory. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.30
CardioboostArm	Uncertain	0.36
BayesDel_addAF	Pathogenic	0.26	D
BayesDel_noAF	Pathogenic	0.14
Cadd	Uncertain	24
Dann	Uncertain	0.99
DEOGEN2	Uncertain	0.69	D
Eigen	Benign	-0.12
Eigen_PC	Benign	-0.064
FATHMM_MKL	Benign	0.71	D
LIST_S2	Uncertain	0.89	D
M_CAP	Pathogenic	0.92	D
MetaRNN	Pathogenic	0.76	D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Benign	1.3	L
MutationTaster	Benign	0.98	D;D
PrimateAI	Pathogenic	0.84	D
PROVEAN	Benign	-0.51	N
REVEL	Pathogenic	0.69
Sift	Benign	0.53	T
Sift4G	Benign	0.27	T
Polyphen		0.0010	B
Vest4		0.47
MutPred		0.82		Gain of relative solvent accessibility (P = 0.09);
MVP		0.99
MPC		1.3
ClinPred		0.73	D
GERP RS		4.4
Varity_R		0.68
gMVP		0.99

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: rs199472846; hg19: chr7-150671937;