rs35940222

Variant names:

• chr14-62707584-TG-T
• rs35940222
• NM_139318.5:c.2890delC

Your query was ambiguous. Multiple possible variants found:

• chr14-62707584-TG-T
• chr14-62707584-TG-TGG

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 0P and 0B.

The NM_139318.5(KCNH5):​c.2890delC​(p.Gln964ArgfsTer59) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000436 in 1,375,762 control chromosomes in the GnomAD database, with no homozygous occurrence. There is a variant allele frequency bias in the population database for this variant (GnomAdExome4), which may indicate mosaicism or somatic mutations in the reference population data. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000044 (0 hom.)
• Consequence: KCNH5 NM_139318.5 frameshift
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.34
• 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: Uncertain_significance. The variant received 0 ACMG points.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCNH5	NM_139318.5	MANE Select	c.2890delC	p.Gln964ArgfsTer59	frameshift	Exon 11 of 11	NP_647479.2
	KCNH5	NM_172375.3		c.*857delC		3_prime_UTR	Exon 10 of 10	NP_758963.1	Q8NCM2-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCNH5	ENST00000322893.12	TSL:1 MANE Select	c.2890delC	p.Gln964ArgfsTer59	frameshift	Exon 11 of 11	ENSP00000321427.7	Q8NCM2-1
	KCNH5	ENST00000420622.6	TSL:1	c.*857delC		3_prime_UTR	Exon 10 of 10	ENSP00000395439.2	Q8NCM2-2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000436 AC: 6 AN: 1375762 Hom.: 0 Cov.: 29 AF XY: 0.00000594 AC XY: 4 AN XY: 673400

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0000325 AC: 1 AN: 30806

American (AMR) AF: 0.00 AC: 0 AN: 33352

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 20910

East Asian (EAS) AF: 0.0000258 AC: 1 AN: 38788

South Asian (SAS) AF: 0.00 AC: 0 AN: 70872

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50476

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5356

European-Non Finnish (NFE) AF: 0.00000374 AC: 4 AN: 1068512

Other (OTH) AF: 0.00 AC: 0 AN: 56690

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000000427158), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Developmental and epileptic encephalopathy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		7.3

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: rs35940222; hg19: chr14-63174302; COSMIC: COSV59767931; COSMIC: COSV59767931;