14-62707584-TG-TGG

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP6_Moderate BS1 BS2

The NM_139318.5(KCNH5):​c.2890dupC​(p.Gln964ProfsTer9) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000733 in 1,527,874 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.000053 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000076 (0 hom.)
• Consequence: KCNH5 NM_139318.5 frameshift
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 7.34
• 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 -10 ACMG points.

• BP6: Variant 14-62707584-T-TG is Benign according to our data. Variant chr14-62707584-T-TG is described in ClinVar as Likely_benign. ClinVar VariationId is 661495.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAdExome4 allele frequency = 0.0000756 (104/1375738) while in subpopulation AFR AF = 0.000195 (6/30806). AF 95% confidence interval is 0.0000847. There are 0 homozygotes in GnomAdExome4. There are 46 alleles in the male GnomAdExome4 subpopulation. Median coverage is 29. This position passed quality control check.
• 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCNH5	NM_139318.5	MANE Select	c.2890dupC	p.Gln964ProfsTer9	frameshift	Exon 11 of 11	NP_647479.2
	KCNH5	NM_172375.3		c.*857dupC		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.2890dupC	p.Gln964ProfsTer9	frameshift	Exon 11 of 11	ENSP00000321427.7	Q8NCM2-1
	KCNH5	ENST00000420622.6	TSL:1	c.*857dupC		3_prime_UTR	Exon 10 of 10	ENSP00000395439.2	Q8NCM2-2

Frequencies

GnomAD3 genomes AF: 0.0000526 AC: 8 AN: 152020 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000725

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000208

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000417 AC: 8 AN: 191874 AF XY: 0.0000296

Gnomad AFR exome AF: 0.000194

Gnomad AMR exome AF: 0.0000408

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000328

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000756 AC: 104 AN: 1375738 Hom.: 0 Cov.: 29 AF XY: 0.0000683 AC XY: 46 AN XY: 673384

African (AFR) AF: 0.000195 AC: 6 AN: 30806

American (AMR) AF: 0.0000300 AC: 1 AN: 33352

Ashkenazi Jewish (ASJ) AF: 0.0000478 AC: 1 AN: 20910

East Asian (EAS) AF: 0.0000516 AC: 2 AN: 38788

South Asian (SAS) AF: 0.0000282 AC: 2 AN: 70880

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50436

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5354

European-Non Finnish (NFE) AF: 0.0000824 AC: 88 AN: 1068522

Other (OTH) AF: 0.0000706 AC: 4 AN: 56690

GnomAD4 genome AF: 0.0000526 AC: 8 AN: 152136 Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1 AN XY: 74370

African (AFR) AF: 0.0000723 AC: 3 AN: 41522

American (AMR) AF: 0.00 AC: 0 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.000208 AC: 1 AN: 4806

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10590

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

European-Non Finnish (NFE) AF: 0.0000588 AC: 4 AN: 67988

Other (OTH) AF: 0.00 AC: 0 AN: 2110

Alfa AF: 0.000174 Hom.: 0

Bravo AF: 0.0000869

ClinVar

ClinVar submissions

Significance: Likely benign

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
Mutation Taster		=11/189	disease causing

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: COSV59762549; COSMIC: COSV59762549;