14-62707587-G-A

Variant names:

• chr14-62707587-G-A
• rs200382362
• NM_139318.5:c.2888C>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_139318.5(KCNH5):​c.2888C>T​(p.Pro963Leu) variant causes a missense change. The variant allele was found at a frequency of 0.000000725 in 1,379,422 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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P963H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.2e-7 (0 hom.)
• Consequence: KCNH5 NM_139318.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.26
• Publications: 0 publications found

Genes affected

KCNH5 (HGNC:6254): (potassium voltage-gated channel subfamily H member 5) This gene encodes a member of voltage-gated potassium channels. Members of this family have diverse functions, including regulating neurotransmitter and hormone release, cardiac function, and cell volume. This protein is an outward-rectifying, noninactivating channel. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jul 2013]

KCNH5 Gene-Disease associations (from GenCC):

• infantile-onset epilepsy

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• developmental and epileptic encephalopathy 112

  Inheritance: AD Classification: STRONG Submitted by: G2P

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.11289963).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNH5	NM_139318.5	c.2888C>T	p.Pro963Leu	missense_variant	Exon 11 of 11	ENST00000322893.12	NP_647479.2
KCNH5	NM_172375.3	c.*855C>T		3_prime_UTR_variant	Exon 10 of 10		NP_758963.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KCNH5	ENST00000322893.12	c.2888C>T	p.Pro963Leu	missense_variant	Exon 11 of 11	1	NM_139318.5	ENSP00000321427.7
KCNH5	ENST00000420622.6	c.*855C>T		3_prime_UTR_variant	Exon 10 of 10	1		ENSP00000395439.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.25e-7 AC: 1 AN: 1379422 Hom.: 0 Cov.: 29 AF XY: 0.00 AC XY: 0 AN XY: 675510

African (AFR) AF: 0.00 AC: 0 AN: 30960

American (AMR) AF: 0.00 AC: 0 AN: 34346

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 21128

East Asian (EAS) AF: 0.00 AC: 0 AN: 38778

South Asian (SAS) AF: 0.00 AC: 0 AN: 71638

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50674

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5366

European-Non Finnish (NFE) AF: 9.35e-7 AC: 1 AN: 1069706

Other (OTH) AF: 0.00 AC: 0 AN: 56826

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Developmental and epileptic encephalopathy Uncertain:1

May 25, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt KCNH5 protein function. This variant has not been reported in the literature in individuals affected with KCNH5-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 963 of the KCNH5 protein (p.Pro963Leu). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.076
BayesDel_addAF	Uncertain	0.076	D
BayesDel_noAF	Benign	-0.13
CADD	Uncertain	24
DANN	Benign	0.95
DEOGEN2	Benign	0.17	T
Eigen	Benign	-0.12
Eigen_PC	Benign	0.10
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.76	T
M_CAP	Benign	0.044	D
MetaRNN	Benign	0.11	T
MetaSVM	Uncertain	0.60	D
MutationAssessor	Benign	1.0	L
PhyloP100		4.3
PrimateAI	Uncertain	0.52	T
PROVEAN	Benign	-1.2	N
REVEL	Uncertain	0.36
Sift	Benign	0.052	T
Sift4G	Benign	0.35	T
Polyphen		0.0	B
Vest4		0.11
MutPred		0.26		Gain of catalytic residue at P966 (P = 0);
MVP		0.43
MPC		0.11
ClinPred		0.57	D
GERP RS		5.4
Varity_R		0.088
gMVP		0.32
Mutation Taster		=76/24	polymorphism

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: rs200382362; hg19: chr14-63174305;