NM_139318.5:c.2888C>A

Variant names:

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

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>A​(p.Pro963His) variant causes a missense change. The variant allele was found at a frequency of 0.00000145 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. P963L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (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=0.1901255).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNH5	NM_139318.5	c.2888C>A	p.Pro963His	missense_variant	Exon 11 of 11	ENST00000322893.12	NP_647479.2
KCNH5	NM_172375.3	c.*855C>A		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>A	p.Pro963His	missense_variant	Exon 11 of 11	1	NM_139318.5	ENSP00000321427.7
KCNH5	ENST00000420622.6	c.*855C>A		3_prime_UTR_variant	Exon 10 of 10	1		ENSP00000395439.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000145 AC: 2 AN: 1379422 Hom.: 0 Cov.: 29 AF XY: 0.00000296 AC XY: 2 AN XY: 675510

African (AFR) AF: 0.0000323 AC: 1 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: 0.000186 AC: 1 AN: 5366

European-Non Finnish (NFE) AF: 0.00 AC: 0 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

Inborn genetic diseases Uncertain:1

Oct 22, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2888C>A (p.P963H) alteration is located in exon 11 (coding exon 11) of the KCNH5 gene. This alteration results from a C to A substitution at nucleotide position 2888, causing the proline (P) at amino acid position 963 to be replaced by a histidine (H). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.071
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Uncertain	-0.060
CADD	Uncertain	23
DANN	Uncertain	0.98
DEOGEN2	Benign	0.16	T
Eigen	Benign	0.18
Eigen_PC	Uncertain	0.32
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.68	T
M_CAP	Benign	0.068	D
MetaRNN	Benign	0.19	T
MetaSVM	Pathogenic	0.79	D
MutationAssessor	Benign	1.0	L
PhyloP100		4.3
PrimateAI	Uncertain	0.51	T
PROVEAN	Benign	-0.66	N
REVEL	Uncertain	0.36
Sift	Uncertain	0.0020	D
Sift4G	Benign	0.15	T
Polyphen		0.65	P
Vest4		0.27
MutPred		0.22		Gain of catalytic residue at P966 (P = 0);
MVP		0.47
MPC		0.20
ClinPred		0.53	D
GERP RS		5.4
Varity_R		0.16
gMVP		0.27
Mutation Taster		=78/22	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;