14-62802493-A-G

Position:

• chr14-62802493-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP2

The NM_139318.5(KCNH5):​c.1658T>C​(p.Leu553Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,206 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
• Consequence: KCNH5 NM_139318.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.32

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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), KCNH5. . Gene score misZ 2.509 (greater than the threshold 3.09). Trascript score misZ 3.7308 (greater than threshold 3.09). GenCC has associacion of gene with infantile-onset epilepsy.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KCNH5	NM_139318.5	c.1658T>C	p.Leu553Ser	missense_variant	9/11	ENST00000322893.12	NP_647479.2
KCNH5	NM_172375.3	c.1658T>C	p.Leu553Ser	missense_variant	9/10		NP_758963.1
KCNH5	XM_047431275.1	c.1658T>C	p.Leu553Ser	missense_variant	9/10		XP_047287231.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KCNH5	ENST00000322893.12	c.1658T>C	p.Leu553Ser	missense_variant	9/11	1	NM_139318.5	ENSP00000321427.7
KCNH5	ENST00000420622.6	c.1658T>C	p.Leu553Ser	missense_variant	9/10	1		ENSP00000395439.2
KCNH5	ENST00000394968.2	c.1484T>C	p.Leu495Ser	missense_variant	9/11	2		ENSP00000378419.1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152206 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 32

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152206 Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1 AN XY: 74356

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.00000378

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

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

May 21, 2019

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. 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 disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has not been reported in the literature in individuals with KCNH5-related disease. This variant is not present in population databases (ExAC no frequency). This sequence change replaces leucine with serine at codon 553 of the KCNH5 protein (p.Leu553Ser). The leucine residue is highly conserved and there is a large physicochemical difference between leucine and serine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.36	D
BayesDel_noAF	Pathogenic	0.28
CADD	Pathogenic	28
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.64	D;.;.
Eigen	Uncertain	0.24
Eigen_PC	Uncertain	0.36
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.96	D;D;D
M_CAP	Uncertain	0.25	D
MetaRNN	Uncertain	0.59	D;D;D
MetaSVM	Uncertain	0.74	D
MutationAssessor	Benign	0.81	L;L;.
PrimateAI	Pathogenic	0.80	T
PROVEAN	Pathogenic	-5.6	D;D;D
REVEL	Pathogenic	0.77
Sift	Benign	0.67	T;T;T
Sift4G	Benign	0.67	T;T;T
Polyphen		1.0	D;B;B
Vest4		0.67
MutPred		0.46		Gain of catalytic residue at F551 (P = 0.0012);Gain of catalytic residue at F551 (P = 0.0012);.;
MVP		0.88
MPC		1.8
ClinPred		1.0	D
GERP RS		5.1
Varity_R		0.41
gMVP		0.52

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

Publications

LitVar

Other links and lift over

dbSNP: rs1406117275; hg19: chr14-63269211;