14-63006481-GAA-GAAA

Variant names:

• chr14-63006481-G-GA
• rs36103415
• NM_139318.5:c.198-10dupT

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.198-10dupT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000454 in 1,466,026 control chromosomes in the GnomAD database, including 4 homozygotes. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0020 (3 hom., cov: 32)
  • Exomes 𝑓: 0.00028 (1 hom.)
• Consequence: KCNH5 NM_139318.5 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.114
• Publications: 2 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 14-63006481-G-GA is Benign according to our data. Variant chr14-63006481-G-GA is described in ClinVar as Benign. ClinVar VariationId is 461388.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.002 (303/151642) while in subpopulation AFR AF = 0.00718 (297/41378). AF 95% confidence interval is 0.00651. There are 3 homozygotes in GnomAd4. There are 138 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 303 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.198-10dupT		intron	N/A	NP_647479.2
	KCNH5	NM_172375.3		c.198-10dupT		intron	N/A	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.198-10_198-9insT		intron	N/A	ENSP00000321427.7	Q8NCM2-1
	KCNH5	ENST00000420622.6	TSL:1	c.198-10_198-9insT		intron	N/A	ENSP00000395439.2	Q8NCM2-2
	KCNH5	ENST00000394964.3	TSL:1	n.363-10_363-9insT		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.00201 AC: 304 AN: 151526 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.00720

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000460

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: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000584 AC: 134 AN: 229392 AF XY: 0.000467

Gnomad AFR exome AF: 0.00763

Gnomad AMR exome AF: 0.000361

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000502

Gnomad NFE exome AF: 0.0000285

Gnomad OTH exome AF: 0.000362

GnomAD4 exome AF: 0.000275 AC: 362 AN: 1314384 Hom.: 1 Cov.: 18 AF XY: 0.000252 AC XY: 166 AN XY: 659712

African (AFR) AF: 0.00789 AC: 237 AN: 30036

American (AMR) AF: 0.000360 AC: 15 AN: 41684

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24726

East Asian (EAS) AF: 0.00 AC: 0 AN: 38680

South Asian (SAS) AF: 0.0000625 AC: 5 AN: 79968

European-Finnish (FIN) AF: 0.0000193 AC: 1 AN: 51802

Middle Eastern (MID) AF: 0.000737 AC: 4 AN: 5426

European-Non Finnish (NFE) AF: 0.0000679 AC: 67 AN: 986898

Other (OTH) AF: 0.000598 AC: 33 AN: 55164

GnomAD4 genome AF: 0.00200 AC: 303 AN: 151642 Hom.: 3 Cov.: 32 AF XY: 0.00186 AC XY: 138 AN XY: 74054

African (AFR) AF: 0.00718 AC: 297 AN: 41378

American (AMR) AF: 0.000394 AC: 6 AN: 15232

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3458

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 4784

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10446

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67878

Other (OTH) AF: 0.00 AC: 0 AN: 2098

Alfa AF: 0.00 Hom.: 14

ClinVar

ClinVar submissions as Germline

Significance: 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		0.11
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: rs36103415; hg19: chr14-63473199;