rs115435938

Variant names:

• chr14-62802531-T-C
• rs115435938
• NM_139318.5:c.1620A>G

Variant summary

Our verdict is Benign. The variant received -15 ACMG points: 0P and 15B. BP4_Strong BP6_Moderate BP7 BS1 BS2

The NM_139318.5(KCNH5):​c.1620A>G​(p.Leu540Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00113 in 1,614,098 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.00094 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0012 (4 hom.)
• Consequence: KCNH5 NM_139318.5 synonymous
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.0300
• 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 -15 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.5).
• BP6: Variant 14-62802531-T-C is Benign according to our data. Variant chr14-62802531-T-C is described in ClinVar as [Benign]. Clinvar id is 461387.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=0.03 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000939 (143/152296) while in subpopulation NFE AF = 0.00146 (99/68022). AF 95% confidence interval is 0.00122. There are 0 homozygotes in GnomAd4. There are 69 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 143 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNH5	NM_139318.5	c.1620A>G	p.Leu540Leu	synonymous_variant	Exon 9 of 11	ENST00000322893.12	NP_647479.2
KCNH5	NM_172375.3	c.1620A>G	p.Leu540Leu	synonymous_variant	Exon 9 of 10		NP_758963.1
KCNH5	XM_047431275.1	c.1620A>G	p.Leu540Leu	synonymous_variant	Exon 9 of 10		XP_047287231.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KCNH5	ENST00000322893.12	c.1620A>G	p.Leu540Leu	synonymous_variant	Exon 9 of 11	1	NM_139318.5	ENSP00000321427.7
KCNH5	ENST00000420622.6	c.1620A>G	p.Leu540Leu	synonymous_variant	Exon 9 of 10	1		ENSP00000395439.2
KCNH5	ENST00000394968.2	c.1446A>G	p.Leu482Leu	synonymous_variant	Exon 9 of 11	2		ENSP00000378419.1

Frequencies

GnomAD3 genomes AF: 0.000940 AC: 143 AN: 152178 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00124

Gnomad ASJ AF: 0.00548

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000941

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00146

Gnomad OTH AF: 0.000955

GnomAD2 exomes AF: 0.000993 AC: 249 AN: 250868 AF XY: 0.000929

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.000782

Gnomad ASJ exome AF: 0.00358

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.00153

Gnomad OTH exome AF: 0.00147

GnomAD4 exome AF: 0.00115 AC: 1683 AN: 1461802 Hom.: 4 Cov.: 32 AF XY: 0.00116 AC XY: 847 AN XY: 727208

African (AFR) AF: 0.000209 AC: 7 AN: 33478

American (AMR) AF: 0.000939 AC: 42 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.00352 AC: 92 AN: 26128

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

South Asian (SAS) AF: 0.0000348 AC: 3 AN: 86258

European-Finnish (FIN) AF: 0.0000187 AC: 1 AN: 53410

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00131 AC: 1458 AN: 1111966

Other (OTH) AF: 0.00132 AC: 80 AN: 60394

GnomAD4 genome AF: 0.000939 AC: 143 AN: 152296 Hom.: 0 Cov.: 32 AF XY: 0.000926 AC XY: 69 AN XY: 74480

African (AFR) AF: 0.0000722 AC: 3 AN: 41560

American (AMR) AF: 0.00124 AC: 19 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.00548 AC: 19 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.0000941 AC: 1 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00146 AC: 99 AN: 68022

Other (OTH) AF: 0.000945 AC: 2 AN: 2116

Alfa AF: 0.00146 Hom.: 0

Bravo AF: 0.00112

EpiCase AF: 0.00191

EpiControl AF: 0.00249

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Developmental and epileptic encephalopathy Benign:1

Feb 02, 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
BayesDel_noAF	Benign	-0.50
CADD	Benign	6.6
DANN	Benign	0.68
PhyloP100		0.030
Mutation Taster		=99/1	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: rs115435938; hg19: chr14-63269249;