14-62855629-A-G

Variant names:

• chr14-62855629-A-G
• rs8012941
• NM_139318.5:c.1370-5777T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_139318.5(KCNH5):​c.1370-5777T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.576 in 152,114 control chromosomes in the GnomAD database, including 27,143 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.58 (27143 hom., cov: 33)
• Consequence: KCNH5 NM_139318.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.344
• Publications: 5 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-1.0).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.797 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNH5	NM_139318.5	c.1370-5777T>C		intron_variant	Intron 7 of 10	ENST00000322893.12	NP_647479.2
KCNH5	NM_172375.3	c.1370-5777T>C		intron_variant	Intron 7 of 9		NP_758963.1
KCNH5	XM_047431275.1	c.1370-5777T>C		intron_variant	Intron 7 of 9		XP_047287231.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KCNH5	ENST00000322893.12	c.1370-5777T>C		intron_variant	Intron 7 of 10	1	NM_139318.5	ENSP00000321427.7
KCNH5	ENST00000420622.6	c.1370-5777T>C		intron_variant	Intron 7 of 9	1		ENSP00000395439.2
KCNH5	ENST00000394968.2	c.1196-5777T>C		intron_variant	Intron 7 of 10	2		ENSP00000378419.1

Frequencies

GnomAD3 genomes AF: 0.576 AC: 87578 AN: 151996 Hom.: 27110 Cov.: 33

Gnomad AFR AF: 0.804

Gnomad AMI AF: 0.567

Gnomad AMR AF: 0.433

Gnomad ASJ AF: 0.553

Gnomad EAS AF: 0.582

Gnomad SAS AF: 0.700

Gnomad FIN AF: 0.580

Gnomad MID AF: 0.592

Gnomad NFE AF: 0.461

Gnomad OTH AF: 0.564

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.576 AC: 87652 AN: 152114 Hom.: 27143 Cov.: 33 AF XY: 0.580 AC XY: 43090 AN XY: 74336

African (AFR) AF: 0.804 AC: 33387 AN: 41524

American (AMR) AF: 0.432 AC: 6598 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.553 AC: 1918 AN: 3470

East Asian (EAS) AF: 0.581 AC: 3004 AN: 5166

South Asian (SAS) AF: 0.699 AC: 3372 AN: 4824

European-Finnish (FIN) AF: 0.580 AC: 6113 AN: 10546

Middle Eastern (MID) AF: 0.588 AC: 173 AN: 294

European-Non Finnish (NFE) AF: 0.461 AC: 31373 AN: 67988

Other (OTH) AF: 0.567 AC: 1198 AN: 2114

Alfa AF: 0.497 Hom.: 63485

Bravo AF: 0.569

Asia WGS AF: 0.655 AC: 2279 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	0.90
DANN	Benign	0.59
PhyloP100		-0.34
Mutation Taster		=100/0	polymorphism (auto)

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: rs8012941; hg19: chr14-63322347;