14-62981264-C-T

Variant names:

• chr14-62981264-C-T
• rs752609494
• NM_139318.5:c.550G>A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 0P and 0B.

The NM_139318.5(KCNH5):​c.550G>A​(p.Val184Ile) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000372 in 1,613,676 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: KCNH5 NM_139318.5 missense, splice_region
• Scores: Splicing: ADA: 0.9970
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.85

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNH5	NM_139318.5	c.550G>A	p.Val184Ile	missense_variant, splice_region_variant	Exon 6 of 11	ENST00000322893.12	NP_647479.2
KCNH5	NM_172375.3	c.550G>A	p.Val184Ile	missense_variant, splice_region_variant	Exon 6 of 10		NP_758963.1
KCNH5	XM_047431275.1	c.550G>A	p.Val184Ile	missense_variant, splice_region_variant	Exon 6 of 10		XP_047287231.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KCNH5	ENST00000322893.12	c.550G>A	p.Val184Ile	missense_variant, splice_region_variant	Exon 6 of 11	1	NM_139318.5	ENSP00000321427.7
KCNH5	ENST00000420622.6	c.550G>A	p.Val184Ile	missense_variant, splice_region_variant	Exon 6 of 10	1		ENSP00000395439.2
KCNH5	ENST00000394964.3	n.715G>A		splice_region_variant, non_coding_transcript_exon_variant	Exon 6 of 7	1
KCNH5	ENST00000394968.2	c.376G>A	p.Val126Ile	missense_variant, splice_region_variant	Exon 6 of 11	2		ENSP00000378419.1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152150 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

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

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461408 Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2 AN XY: 727038

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000448

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152268 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 74460

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000378

ExAC AF: 0.0000247 AC: 3

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Early infantile epileptic encephalopathy with suppression bursts Uncertain:1

Jun 22, 2017

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. This sequence change replaces valine with isoleucine at codon 184 of the KCNH5 protein (p.Val184Ile). The valine residue is moderately conserved and there is a small physicochemical difference between valine and isoleucine. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the ExAC database. This variant has not been reported in the literature in individuals with KCNH5-related disease. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_addAF	Uncertain	0.035	T
BayesDel_noAF	Uncertain	-0.010
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Benign	0.17	T;.;.
Eigen	Benign	0.11
Eigen_PC	Uncertain	0.29
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.94	D;D;D
M_CAP	Uncertain	0.23	D
MetaRNN	Benign	0.33	T;T;T
MetaSVM	Pathogenic	0.89	D
MutationAssessor	Uncertain	2.2	M;M;.
PrimateAI	Uncertain	0.68	T
PROVEAN	Benign	-0.42	N;N;N
REVEL	Uncertain	0.48
Sift	Benign	0.077	T;T;T
Sift4G	Benign	0.12	T;T;T
Polyphen		0.079	B;B;B
Vest4		0.30
MutPred		0.36		Loss of sheet (P = 0.0457);Loss of sheet (P = 0.0457);.;
MVP		0.82
MPC		0.68
ClinPred		0.35	T
GERP RS		5.3
Varity_R		0.12
gMVP		0.42

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.80
SpliceAI score (max)		0.080		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs752609494; hg19: chr14-63447982;