chr7-150952720-G-T

Position:

• chr7-150952720-G-T

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1 PM2 PM5 PP3_Moderate PP5_Moderate

The ENST00000262186.10(KCNH2):​c.1262C>A​(p.Thr421Lys) variant causes a missense change involving the alteration of a 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 Pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T421M) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: KCNH2 ENST00000262186.10 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 9.81

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 Pathogenic. Variant got 10 ACMG points.

• PM1: In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 7 uncertain in ENST00000262186.10
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr7-150952720-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 67173.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, Uncertain_significance=2, not_provided=1}.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.928
• PP5: Variant 7-150952720-G-T is Pathogenic according to our data. Variant chr7-150952720-G-T is described in ClinVar as [Pathogenic]. Clinvar id is 200331.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KCNH2	NM_000238.4	c.1262C>A	p.Thr421Lys	missense_variant	6/15	ENST00000262186.10	NP_000229.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KCNH2	ENST00000262186.10	c.1262C>A	p.Thr421Lys	missense_variant	6/15	1	NM_000238.4	ENSP00000262186	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Mar 31, 2013

p.Thr421Lys (ACG>AAG): c.1262 C>A in exon 6 of the KCNH2 (aka HERG) gene (NM_000238.2)While the Thr421Lys mutation in the KCNH2 gene has not been reported to our knowledge, a mutation affecting this same codon, Thr421Met, has been reported in association with LQTS (Tester D et al., 2005). Additionally, mutations in nearby residues (Leu413Pro, Tyr420Cys, Ala422Thr) have been reported in association with LQTS, further supporting the functional importance of this codon and this region of the protein. Thr421Lys results in a semi-conservative amino acid substitution of a neutral, polar Threonine with a positively charged Lysine at a position that is conserved across species. In silico analysis predicts Thr421Lys is probably damaging to the protein structure/function. Furthermore, Thr421Lys was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations.In summary, Thr421Lys in the KCNH2 gene is interpreted as a likely disease-causing mutation. The variant is found in LQT panel(s). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.55	D
BayesDel_noAF	Pathogenic	0.55
CADD	Pathogenic	29
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.99	.;D;D
Eigen	Pathogenic	0.89
Eigen_PC	Pathogenic	0.81
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.97	D;D;D
M_CAP	Pathogenic	0.82	D
MetaRNN	Pathogenic	0.93	D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.4	.;M;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Pathogenic	0.87	D
PROVEAN	Pathogenic	-5.7	D;D;N
REVEL	Pathogenic	0.95
Sift	Pathogenic	0.0	D;D;T
Sift4G	Benign	0.062	T;T;T
Polyphen		0.91	P;D;.
Vest4		0.94
MutPred		0.71		.;Gain of ubiquitination at T421 (P = 0.0267);.;
MVP		1.0
MPC		2.4
ClinPred		1.0	D
GERP RS		4.6
Varity_R		0.97
gMVP		0.99

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: rs199472894; hg19: chr7-150649808;