14-62898783-T-C

Variant names:

• chr14-62898783-T-C
• rs10483759
• NM_139318.5:c.1370-48931A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_139318.5(KCNH5):​c.1370-48931A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.124 in 152,076 control chromosomes in the GnomAD database, including 1,354 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.12 (1354 hom., cov: 33)
• Consequence: KCNH5 NM_139318.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.579
• 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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.267 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNH5	NM_139318.5	c.1370-48931A>G		intron_variant	Intron 7 of 10	ENST00000322893.12	NP_647479.2
KCNH5	NM_172375.3	c.1370-48931A>G		intron_variant	Intron 7 of 9		NP_758963.1
KCNH5	XM_047431275.1	c.1370-48931A>G		intron_variant	Intron 7 of 9		XP_047287231.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KCNH5	ENST00000322893.12	c.1370-48931A>G		intron_variant	Intron 7 of 10	1	NM_139318.5	ENSP00000321427.7
KCNH5	ENST00000420622.6	c.1370-48931A>G		intron_variant	Intron 7 of 9	1		ENSP00000395439.2
KCNH5	ENST00000394968.2	c.1196-48931A>G		intron_variant	Intron 7 of 10	2		ENSP00000378419.1

Frequencies

GnomAD3 genomes AF: 0.124 AC: 18816 AN: 151960 Hom.: 1350 Cov.: 33

Gnomad AFR AF: 0.106

Gnomad AMI AF: 0.0921

Gnomad AMR AF: 0.187

Gnomad ASJ AF: 0.177

Gnomad EAS AF: 0.278

Gnomad SAS AF: 0.0736

Gnomad FIN AF: 0.0790

Gnomad MID AF: 0.151

Gnomad NFE AF: 0.116

Gnomad OTH AF: 0.150

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.124 AC: 18839 AN: 152076 Hom.: 1354 Cov.: 33 AF XY: 0.125 AC XY: 9270 AN XY: 74336

African (AFR) AF: 0.106 AC: 4421 AN: 41514

American (AMR) AF: 0.187 AC: 2854 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.177 AC: 614 AN: 3472

East Asian (EAS) AF: 0.279 AC: 1441 AN: 5160

South Asian (SAS) AF: 0.0742 AC: 358 AN: 4822

European-Finnish (FIN) AF: 0.0790 AC: 836 AN: 10586

Middle Eastern (MID) AF: 0.152 AC: 44 AN: 290

European-Non Finnish (NFE) AF: 0.116 AC: 7870 AN: 67932

Other (OTH) AF: 0.150 AC: 317 AN: 2110

Alfa AF: 0.0998 Hom.: 465

Bravo AF: 0.139

Asia WGS AF: 0.175 AC: 606 AN: 3456

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	3.7
DANN	Benign	0.50
PhyloP100		0.58
Mutation Taster		=100/0	polymorphism (auto)

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: rs10483759; hg19: chr14-63365501;