14-62707527-T-C

Position:

• chr14-62707527-T-C

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 3P and 4B. PM2 PP2 BP4_Moderate BP6_Moderate

The NM_139318.5(KCNH5):​c.2948A>G​(p.Lys983Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: KCNH5 NM_139318.5 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 3.12

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 Likely_benign. Variant got -1 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.
• BP4: Computational evidence support a benign effect (MetaRNN=0.10174361).
• BP6: Variant 14-62707527-T-C is Benign according to our data. Variant chr14-62707527-T-C is described in ClinVar as [Benign]. Clinvar id is 962491.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KCNH5	NM_139318.5	c.2948A>G	p.Lys983Arg	missense_variant	11/11	ENST00000322893.12	NP_647479.2
KCNH5	NM_172375.3	c.*915A>G		3_prime_UTR_variant	10/10		NP_758963.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KCNH5	ENST00000322893.12	c.2948A>G	p.Lys983Arg	missense_variant	11/11	1	NM_139318.5	ENSP00000321427	P1
KCNH5	ENST00000420622.6			downstream_gene_variant		1		ENSP00000395439

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 27

GnomAD4 genome Cov.: 32

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Early infantile epileptic encephalopathy with suppression bursts Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Mar 18, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.068
BayesDel_addAF	Uncertain	0.057	T
BayesDel_noAF	Benign	-0.16
CADD	Benign	21
DANN	Benign	0.36
DEOGEN2	Benign	0.10	T
Eigen	Benign	-0.16
Eigen_PC	Benign	0.073
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.60	T
M_CAP	Benign	0.021	T
MetaRNN	Benign	0.10	T
MetaSVM	Uncertain	0.71	D
MutationAssessor	Benign	1.0	L
MutationTaster	Benign	0.99	D
PrimateAI	Uncertain	0.62	T
PROVEAN	Benign	-0.38	N
REVEL	Uncertain	0.39
Sift	Benign	0.53	T
Sift4G	Benign	1.0	T
Polyphen		0.0020	B
Vest4		0.15
MutPred		0.22		Loss of ubiquitination at K983 (P = 3e-04);
MVP		0.64
MPC		0.089
ClinPred		0.72	D
GERP RS		5.4
Varity_R		0.098
gMVP		0.27

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: rs1271834396; hg19: chr14-63174245;