rs1339742380

Variant names:

• chr7-150946911-G-A
• rs1339742380
• NM_000238.4:c.3296C>T

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 1P and 5B. PP2 BP4 BS2

The NM_000238.4(KCNH2):​c.3296C>T​(p.Pro1099Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00000691 in 1,446,672 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 Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. P1099P) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000069 (0 hom.)
• Consequence: KCNH2 NM_000238.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.79
• Publications: 0 publications found

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]

KCNH2 Gene-Disease associations (from GenCC):

• long QT syndrome

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• long QT syndrome 2

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P
• short QT syndrome

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen
• short QT syndrome type 1

  Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
• Brugada syndrome

  Inheritance: AD Classification: MODERATE, NO_KNOWN Submitted by: ClinGen, Genomics England PanelApp

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 158 curated pathogenic missense variants (we use a threshold of 10). The gene has 38 curated benign missense variants. Gene score misZ: 3.3724 (above the threshold of 3.09). Trascript score misZ: 2.4846 (below the threshold of 3.09). GenCC associations: The gene is linked to long QT syndrome 2, Brugada syndrome, short QT syndrome type 1, short QT syndrome, long QT syndrome.
• BP4: Computational evidence support a benign effect (MetaRNN=0.3849167).
• BS2: High AC in GnomAdExome4 at 10 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNH2	NM_000238.4	c.3296C>T	p.Pro1099Leu	missense_variant	Exon 14 of 15	ENST00000262186.10	NP_000229.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KCNH2	ENST00000262186.10	c.3296C>T	p.Pro1099Leu	missense_variant	Exon 14 of 15	1	NM_000238.4	ENSP00000262186.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000829 AC: 2 AN: 241314 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000298

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000548

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000691 AC: 10 AN: 1446672 Hom.: 0 Cov.: 32 AF XY: 0.00000418 AC XY: 3 AN XY: 717200

African (AFR) AF: 0.00 AC: 0 AN: 33252

American (AMR) AF: 0.0000228 AC: 1 AN: 43868

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25380

East Asian (EAS) AF: 0.0000254 AC: 1 AN: 39368

South Asian (SAS) AF: 0.0000118 AC: 1 AN: 84470

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52848

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5688

European-Non Finnish (NFE) AF: 0.00000544 AC: 6 AN: 1102094

Other (OTH) AF: 0.0000167 AC: 1 AN: 59704

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Long QT syndrome Uncertain:1

Oct 30, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 1099 of the KCNH2 protein (p.Pro1099Leu). This variant is present in population databases (no rsID available, gnomAD 0.006%). This variant has not been reported in the literature in individuals affected with KCNH2-related conditions. ClinVar contains an entry for this variant (Variation ID: 526951). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.090
CardioboostArm	Benign	0.0011
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Uncertain	0.10
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.68	.;D
Eigen	Benign	0.13
Eigen_PC	Uncertain	0.25
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Uncertain	0.87	D;D
M_CAP	Pathogenic	0.74	D
MetaRNN	Benign	0.38	T;T
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Benign	1.5	.;L
PhyloP100		3.8
PrimateAI	Uncertain	0.57	T
PROVEAN	Uncertain	-3.0	D;D
REVEL	Uncertain	0.57
Sift	Uncertain	0.0070	D;D
Sift4G	Uncertain	0.023	D;D
Polyphen		0.57	P;B
Vest4		0.39
MutPred		0.18		.;Loss of loop (P = 0.0288);
MVP		0.87
MPC		0.69
ClinPred		0.89	D
GERP RS		4.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.7
Varity_R		0.24
gMVP		0.57
Mutation Taster		=23/77	disease causing

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

Other links and lift over

dbSNP: rs1339742380; hg19: chr7-150643999; COSMIC: COSV51127971; COSMIC: COSV51127971;