14-63006481-GAA-GA

Variant names:

• chr14-63006481-GA-G
• rs36103415
• NM_139318.5:c.198-10delT

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP6_Moderate BA1

The NM_139318.5(KCNH5):​c.198-10delT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0432 in 1,465,854 control chromosomes in the GnomAD database, including 1,568 homozygotes. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.048 (203 hom., cov: 32)
  • Exomes 𝑓: 0.043 (1365 hom.)
• Consequence: KCNH5 NM_139318.5 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.114
• Publications: 2 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 -10 ACMG points.

• BP6: Variant 14-63006481-GA-G is Benign according to our data. Variant chr14-63006481-GA-G is described in ClinVar as Benign. ClinVar VariationId is 241862.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0571 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNH5	NM_139318.5	c.198-10delT		intron_variant	Intron 2 of 10	ENST00000322893.12	NP_647479.2
KCNH5	NM_172375.3	c.198-10delT		intron_variant	Intron 2 of 9		NP_758963.1
KCNH5	XM_047431275.1	c.198-10delT		intron_variant	Intron 2 of 9		XP_047287231.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KCNH5	ENST00000322893.12	c.198-10delT		intron_variant	Intron 2 of 10	1	NM_139318.5	ENSP00000321427.7
KCNH5	ENST00000420622.6	c.198-10delT		intron_variant	Intron 2 of 9	1		ENSP00000395439.2
KCNH5	ENST00000394964.3	n.363-10delT		intron_variant	Intron 2 of 6	1
KCNH5	ENST00000394968.2	c.24-10delT		intron_variant	Intron 2 of 10	2		ENSP00000378419.1

Frequencies

GnomAD3 genomes AF: 0.0479 AC: 7256 AN: 151510 Hom.: 202 Cov.: 32

Gnomad AFR AF: 0.0485

Gnomad AMI AF: 0.102

Gnomad AMR AF: 0.0356

Gnomad ASJ AF: 0.0188

Gnomad EAS AF: 0.0630

Gnomad SAS AF: 0.0217

Gnomad FIN AF: 0.0917

Gnomad MID AF: 0.0222

Gnomad NFE AF: 0.0454

Gnomad OTH AF: 0.0376

GnomAD2 exomes AF: 0.0468 AC: 10735 AN: 229392 AF XY: 0.0450

Gnomad AFR exome AF: 0.0506

Gnomad AMR exome AF: 0.0309

Gnomad ASJ exome AF: 0.0244

Gnomad EAS exome AF: 0.0700

Gnomad FIN exome AF: 0.0887

Gnomad NFE exome AF: 0.0484

Gnomad OTH exome AF: 0.0430

GnomAD4 exome AF: 0.0427 AC: 56092 AN: 1314228 Hom.: 1365 Cov.: 18 AF XY: 0.0421 AC XY: 27752 AN XY: 659622

African (AFR) AF: 0.0495 AC: 1485 AN: 30030

American (AMR) AF: 0.0298 AC: 1242 AN: 41688

Ashkenazi Jewish (ASJ) AF: 0.0212 AC: 524 AN: 24726

East Asian (EAS) AF: 0.0528 AC: 2043 AN: 38684

South Asian (SAS) AF: 0.0170 AC: 1357 AN: 79972

European-Finnish (FIN) AF: 0.0830 AC: 4300 AN: 51804

Middle Eastern (MID) AF: 0.0190 AC: 103 AN: 5424

European-Non Finnish (NFE) AF: 0.0435 AC: 42886 AN: 986736

Other (OTH) AF: 0.0390 AC: 2152 AN: 55164

GnomAD4 genome AF: 0.0479 AC: 7258 AN: 151626 Hom.: 203 Cov.: 32 AF XY: 0.0494 AC XY: 3658 AN XY: 74040

African (AFR) AF: 0.0485 AC: 2006 AN: 41376

American (AMR) AF: 0.0356 AC: 542 AN: 15230

Ashkenazi Jewish (ASJ) AF: 0.0188 AC: 65 AN: 3458

East Asian (EAS) AF: 0.0627 AC: 324 AN: 5166

South Asian (SAS) AF: 0.0217 AC: 104 AN: 4784

European-Finnish (FIN) AF: 0.0917 AC: 958 AN: 10442

Middle Eastern (MID) AF: 0.0238 AC: 7 AN: 294

European-Non Finnish (NFE) AF: 0.0454 AC: 3082 AN: 67870

Other (OTH) AF: 0.0367 AC: 77 AN: 2098

Alfa AF: 0.0232 Hom.: 14

Bravo AF: 0.0445

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Developmental and epileptic encephalopathy Benign:1

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.11
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: rs36103415; hg19: chr14-63473199; COSMIC: COSV59753458;