NM_139318.5:c.198-3dupC

Variant names:

• chr14-63006474-T-TG
• rs752865520
• NM_139318.5:c.198-3dupC

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP6_Very_Strong BS2

The NM_139318.5(KCNH5):​c.198-3dupC variant causes a splice region, intron change. The variant allele was found at a frequency of 0.000055 in 1,564,528 control chromosomes in the GnomAD database, with no homozygous occurrence. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.000053 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000055 (0 hom.)
• Consequence: KCNH5 NM_139318.5 splice_region, intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 6.83
• 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.

• BP6: Variant 14-63006474-T-TG is Benign according to our data. Variant chr14-63006474-T-TG is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 1170383.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAd4 at 8 AD gene.

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.198-3dupC		splice_region intron	N/A	NP_647479.2
	KCNH5	NM_172375.3		c.198-3dupC		splice_region intron	N/A	NP_758963.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCNH5	ENST00000322893.12	TSL:1 MANE Select	c.198-3_198-2insC		splice_region intron	N/A	ENSP00000321427.7
	KCNH5	ENST00000420622.6	TSL:1	c.198-3_198-2insC		splice_region intron	N/A	ENSP00000395439.2
	KCNH5	ENST00000394964.3	TSL:1	n.363-3_363-2insC		splice_region intron	N/A

Frequencies

GnomAD3 genomes AF: 0.0000529 AC: 8 AN: 151262 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000243

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000885

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000293 AC: 7 AN: 238760 AF XY: 0.0000387

Gnomad AFR exome AF: 0.0000632

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.000209

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000366

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000552 AC: 78 AN: 1413266 Hom.: 0 Cov.: 23 AF XY: 0.0000468 AC XY: 33 AN XY: 704984

African (AFR) AF: 0.00 AC: 0 AN: 32386

American (AMR) AF: 0.00 AC: 0 AN: 43272

Ashkenazi Jewish (ASJ) AF: 0.000429 AC: 11 AN: 25624

East Asian (EAS) AF: 0.0000254 AC: 1 AN: 39334

South Asian (SAS) AF: 0.0000240 AC: 2 AN: 83426

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52686

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5652

European-Non Finnish (NFE) AF: 0.0000569 AC: 61 AN: 1072258

Other (OTH) AF: 0.0000512 AC: 3 AN: 58628

GnomAD4 genome AF: 0.0000529 AC: 8 AN: 151262 Hom.: 0 Cov.: 33 AF XY: 0.0000406 AC XY: 3 AN XY: 73866

African (AFR) AF: 0.0000243 AC: 1 AN: 41116

American (AMR) AF: 0.00 AC: 0 AN: 15186

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5166

South Asian (SAS) AF: 0.00 AC: 0 AN: 4818

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10448

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000885 AC: 6 AN: 67768

Other (OTH) AF: 0.00 AC: 0 AN: 2076

Alfa AF: 0.0000868 Hom.: 0

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Feb 16, 2025

Laboratory of Genetics, Children's Clinical University Hospital Latvia

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Developmental and epileptic encephalopathy Benign:1

Oct 28, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

KCNH5-related disorder Benign:1

Oct 14, 2020

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		6.8

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: rs752865520; hg19: chr14-63473192;