rs142252600

Variant names:

• chr14-62987093-A-G
• rs142252600
• NM_139318.5:c.528T>C

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_139318.5(KCNH5):​c.528T>C​(p.His176His) variant causes a synonymous change. The variant allele was found at a frequency of 0.000661 in 1,613,086 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.00047 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00068 (1 hom.)
• Consequence: KCNH5 NM_139318.5 synonymous
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 5.05
• Publications: 1 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.52).
• BP6: Variant 14-62987093-A-G is Benign according to our data. Variant chr14-62987093-A-G is described in ClinVar as Likely_benign. ClinVar VariationId is 416116.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000473 (72/152196) while in subpopulation NFE AF = 0.000823 (56/68030). AF 95% confidence interval is 0.000651. There are 0 homozygotes in GnomAd4. There are 30 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High AC in GnomAd4 at 72 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNH5	NM_139318.5	c.528T>C	p.His176His	synonymous_variant	Exon 5 of 11	ENST00000322893.12	NP_647479.2
KCNH5	NM_172375.3	c.528T>C	p.His176His	synonymous_variant	Exon 5 of 10		NP_758963.1
KCNH5	XM_047431275.1	c.528T>C	p.His176His	synonymous_variant	Exon 5 of 10		XP_047287231.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KCNH5	ENST00000322893.12	c.528T>C	p.His176His	synonymous_variant	Exon 5 of 11	1	NM_139318.5	ENSP00000321427.7
KCNH5	ENST00000420622.6	c.528T>C	p.His176His	synonymous_variant	Exon 5 of 10	1		ENSP00000395439.2
KCNH5	ENST00000394964.3	n.693T>C		non_coding_transcript_exon_variant	Exon 5 of 7	1
KCNH5	ENST00000394968.2	c.354T>C	p.His118His	synonymous_variant	Exon 5 of 11	2		ENSP00000378419.1

Frequencies

GnomAD3 genomes AF: 0.000473 AC: 72 AN: 152196 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000338

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000823

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000275 AC: 69 AN: 251244 AF XY: 0.000302

Gnomad AFR exome AF: 0.000246

Gnomad AMR exome AF: 0.0000290

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000546

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.000680 AC: 994 AN: 1460890 Hom.: 1 Cov.: 30 AF XY: 0.000676 AC XY: 491 AN XY: 726824

African (AFR) AF: 0.000180 AC: 6 AN: 33424

American (AMR) AF: 0.0000224 AC: 1 AN: 44684

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26100

East Asian (EAS) AF: 0.00 AC: 0 AN: 39682

South Asian (SAS) AF: 0.00 AC: 0 AN: 86222

European-Finnish (FIN) AF: 0.0000187 AC: 1 AN: 53412

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.000869 AC: 966 AN: 1111230

Other (OTH) AF: 0.000331 AC: 20 AN: 60372

GnomAD4 genome AF: 0.000473 AC: 72 AN: 152196 Hom.: 0 Cov.: 33 AF XY: 0.000403 AC XY: 30 AN XY: 74352

African (AFR) AF: 0.000338 AC: 14 AN: 41460

American (AMR) AF: 0.0000655 AC: 1 AN: 15264

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.00 AC: 0 AN: 4836

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

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

European-Non Finnish (NFE) AF: 0.000823 AC: 56 AN: 68030

Other (OTH) AF: 0.000478 AC: 1 AN: 2092

Alfa AF: 0.000687 Hom.: 0

Bravo AF: 0.000389

EpiCase AF: 0.000655

EpiControl AF: 0.000593

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Developmental and epileptic encephalopathy Benign:1

Jan 14, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely 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
BayesDel_noAF	Benign	-0.52
CADD	Benign	7.5
DANN	Benign	0.62
PhyloP100		5.0
Mutation Taster		=100/0	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: rs142252600; hg19: chr14-63453811; COSMIC: COSV59755871;