14-62707548-G-A

Variant names:

• chr14-62707548-G-A
• rs2139898259
• NM_139318.5:c.2927C>T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_139318.5(KCNH5):​c.2927C>T​(p.Pro976Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000267 in 1,495,936 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 (★).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000022 (0 hom.)
• Consequence: KCNH5 NM_139318.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.12
• 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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.28991365).

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCNH5	NM_139318.5	MANE Select	c.2927C>T	p.Pro976Leu	missense	Exon 11 of 11	NP_647479.2
	KCNH5	NM_172375.3		c.*894C>T		3_prime_UTR	Exon 10 of 10	NP_758963.1	Q8NCM2-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCNH5	ENST00000322893.12	TSL:1 MANE Select	c.2927C>T	p.Pro976Leu	missense	Exon 11 of 11	ENSP00000321427.7	Q8NCM2-1
	KCNH5	ENST00000420622.6	TSL:1	c.*894C>T		downstream_gene	N/A	ENSP00000395439.2	Q8NCM2-2

Frequencies

GnomAD3 genomes AF: 0.00000658 AC: 1 AN: 152048 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000223 AC: 3 AN: 1343774 Hom.: 0 Cov.: 29 AF XY: 0.00000153 AC XY: 1 AN XY: 655062

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 30006

American (AMR) AF: 0.00 AC: 0 AN: 28112

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19582

East Asian (EAS) AF: 0.00 AC: 0 AN: 38412

South Asian (SAS) AF: 0.0000476 AC: 3 AN: 63002

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49224

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5262

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1054826

Other (OTH) AF: 0.00 AC: 0 AN: 55348

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.0000416442), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152162 Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1 AN XY: 74400

African (AFR) AF: 0.00 AC: 0 AN: 41496

American (AMR) AF: 0.00 AC: 0 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10596

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68004

Other (OTH) AF: 0.00 AC: 0 AN: 2106

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Developmental and epileptic encephalopathy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Pathogenic	0.30	D
BayesDel_noAF	Pathogenic	0.20
CADD	Benign	23
DANN	Benign	0.96
DEOGEN2	Uncertain	0.58	D
Eigen	Benign	0.12
Eigen_PC	Uncertain	0.31
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.96	D
M_CAP	Uncertain	0.086	D
MetaRNN	Benign	0.29	T
MetaSVM	Pathogenic	0.84	D
MutationAssessor	Benign	1.6	L
PhyloP100		8.1
PrimateAI	Uncertain	0.72	T
PROVEAN	Uncertain	-2.7	D
REVEL	Uncertain	0.55
Sift	Benign	0.055	T
Sift4G	Benign	0.091	T
Polyphen		0.18	B
Vest4		0.58
MutPred		0.18		Loss of glycosylation at P976 (P = 0.0289)
MVP		0.75
MPC		0.11
ClinPred		0.88	D
GERP RS		5.4
Varity_R		0.22
gMVP		0.56
Mutation Taster		=65/35	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: rs2139898259; hg19: chr14-63174266;