14-62707647-G-C

Variant names:

• chr14-62707647-G-C
• rs761523326
• NM_139318.5:c.2828C>G

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_139318.5(KCNH5):​c.2828C>G​(p.Ser943Trp) variant causes a missense change. The variant allele was found at a frequency of 0.00000279 in 1,431,620 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S943L) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000028 (0 hom.)
• Consequence: KCNH5 NM_139318.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.71
• 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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.764

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_139318.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCNH5	NM_139318.5	MANE Select	c.2828C>G	p.Ser943Trp	missense	Exon 11 of 11	NP_647479.2
	KCNH5	NM_172375.3		c.*795C>G		3_prime_UTR	Exon 10 of 10	NP_758963.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCNH5	ENST00000322893.12	TSL:1 MANE Select	c.2828C>G	p.Ser943Trp	missense	Exon 11 of 11	ENSP00000321427.7
	KCNH5	ENST00000420622.6	TSL:1	c.*795C>G		3_prime_UTR	Exon 10 of 10	ENSP00000395439.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000279 AC: 4 AN: 1431620 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 707524

African (AFR) AF: 0.00 AC: 0 AN: 32434

American (AMR) AF: 0.00 AC: 0 AN: 41788

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24642

East Asian (EAS) AF: 0.00 AC: 0 AN: 39102

South Asian (SAS) AF: 0.00 AC: 0 AN: 83302

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52840

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5610

European-Non Finnish (NFE) AF: 0.00000366 AC: 4 AN: 1093036

Other (OTH) AF: 0.00 AC: 0 AN: 58866

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.25
BayesDel_addAF	Pathogenic	0.31	D
BayesDel_noAF	Pathogenic	0.21
CADD	Pathogenic	26
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.51	D
Eigen	Uncertain	0.51
Eigen_PC	Uncertain	0.53
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.90	D
M_CAP	Uncertain	0.22	D
MetaRNN	Pathogenic	0.76	D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Benign	1.8	L
PhyloP100		4.7
PrimateAI	Uncertain	0.58	T
PROVEAN	Uncertain	-3.1	D
REVEL	Pathogenic	0.70
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.010	D
Polyphen		0.99	D
Vest4		0.56
MutPred		0.33		Loss of disorder (P = 0.0036)
MVP		0.78
MPC		0.49
ClinPred		0.97	D
GERP RS		5.1
Varity_R		0.59
gMVP		0.56
Mutation Taster		=79/21	polymorphism

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

Other links and lift over

dbSNP: rs761523326; hg19: chr14-63174365;