14-62707615-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.2860A>G(p.Lys954Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000143 in 1,398,348 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: KCNH5 NM_139318.5 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.60

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 where missense usually causes diseases, KCNH5
• BP4: Computational evidence support a benign effect (MetaRNN=0.080265015).
• BP6: Variant 14-62707615-T-C is Benign according to our data. Variant chr14-62707615-T-C is described in ClinVar as [Benign]. Clinvar id is 1426513.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KCNH5	NM_139318.5	c.2860A>G	p.Lys954Glu	missense_variant	11/11	ENST00000322893.12
KCNH5	NM_172375.3	c.*827A>G		3_prime_UTR_variant	10/10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KCNH5	ENST00000322893.12	c.2860A>G	p.Lys954Glu	missense_variant	11/11	1	NM_139318.5	P1
KCNH5	ENST00000420622.6	c.*827A>G		3_prime_UTR_variant	10/10	1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000143 AC: 2 AN: 1398348 Hom.: 0 Cov.: 29 AF XY: 0.00000146 AC XY: 1 AN XY: 686830

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000266

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.28e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

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

Invitae

Nov 15, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.085
BayesDel_addAF	Uncertain	0.049	T
BayesDel_noAF	Benign	-0.17
Cadd	Benign	17
Dann	Benign	0.97
DEOGEN2	Benign	0.11	T
Eigen	Benign	-0.53
Eigen_PC	Benign	-0.34
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.33	T
M_CAP	Benign	0.085	D
MetaRNN	Benign	0.080	T
MetaSVM	Uncertain	0.41	D
MutationAssessor	Benign	0.0	N
MutationTaster	Benign	1.0	D;N
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-0.52	N
REVEL	Uncertain	0.44
Sift	Benign	0.13	T
Sift4G	Benign	0.71	T
Polyphen		0.0	B
Vest4		0.083
MutPred		0.20		Loss of ubiquitination at K954 (P = 0.0022);
MVP		0.42
MPC		0.16
ClinPred		0.12	T
GERP RS		4.4
Varity_R		0.11
gMVP		0.23

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: rs1884461774; hg19: chr14-63174333;