14-62707585-G-T

Variant names:

• chr14-62707585-G-T
• rs753525158
• NM_139318.5:c.2890C>A

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Moderate BP6_Moderate BS2

The ENST00000322893.12(KCNH5):​c.2890C>A​(p.Gln964Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000218 in 1,375,954 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q964E) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000022 (0 hom.)
• Consequence: KCNH5 ENST00000322893.12 missense
• Clinical Significance: Benign criteria provided, single submitter B: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: Benign. The variant received -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.15771776).
• BP6: Variant 14-62707585-G-T is Benign according to our data. Variant chr14-62707585-G-T is described in ClinVar as Benign. ClinVar VariationId is 241863.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High AC in GnomAdExome4 at 30 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000322893.12. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCNH5	NM_139318.5	MANE Select	c.2890C>A	p.Gln964Lys	missense	Exon 11 of 11	NP_647479.2
	KCNH5	NM_172375.3		c.*857C>A		3_prime_UTR	Exon 10 of 10	NP_758963.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCNH5	ENST00000322893.12	TSL:1 MANE Select	c.2890C>A	p.Gln964Lys	missense	Exon 11 of 11	ENSP00000321427.7
	KCNH5	ENST00000420622.6	TSL:1	c.*857C>A		3_prime_UTR	Exon 10 of 10	ENSP00000395439.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000103 AC: 2 AN: 194438 AF XY: 0.0000195

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000217

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000218 AC: 30 AN: 1375954 Hom.: 0 Cov.: 29 AF XY: 0.0000282 AC XY: 19 AN XY: 673614

African (AFR) AF: 0.00 AC: 0 AN: 30864

American (AMR) AF: 0.00 AC: 0 AN: 33976

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 21014

East Asian (EAS) AF: 0.00 AC: 0 AN: 38734

South Asian (SAS) AF: 0.00 AC: 0 AN: 70882

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50548

Middle Eastern (MID) AF: 0.000187 AC: 1 AN: 5352

European-Non Finnish (NFE) AF: 0.0000253 AC: 27 AN: 1067828

Other (OTH) AF: 0.0000352 AC: 2 AN: 56756

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.00000827 AC: 1

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
AlphaMissense	Benign	0.062
BayesDel_addAF	Uncertain	0.053	T
BayesDel_noAF	Benign	-0.13
CADD	Benign	19
DANN	Benign	0.72
DEOGEN2	Benign	0.085	T
Eigen	Benign	-0.30
Eigen_PC	Benign	-0.0098
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.67	T
M_CAP	Benign	0.074	D
MetaRNN	Benign	0.16	T
MetaSVM	Uncertain	0.42	D
MutationAssessor	Benign	0.14	N
PhyloP100		7.3
PrimateAI	Uncertain	0.53	T
PROVEAN	Benign	0.040	N
REVEL	Uncertain	0.41
Sift	Benign	0.35	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.23
MutPred		0.32		Gain of catalytic residue at P966 (P = 0)
MVP		0.51
MPC		0.14
ClinPred		0.36	T
GERP RS		5.4
Varity_R		0.21
gMVP		0.14
Mutation Taster		=83/17	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: rs753525158; hg19: chr14-63174303; COSMIC: COSV59763617; COSMIC: COSV59763617;