chr14-62707591-G-T

Position:

• chr14-62707591-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2 PP2 BP4

The NM_139318.5(KCNH5):​c.2884C>A​(p.Pro962Thr) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: KCNH5 NM_139318.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.36

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 2 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=0.33723497).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KCNH5	NM_139318.5	c.2884C>A	p.Pro962Thr	missense_variant	11/11	ENST00000322893.12	NP_647479.2
KCNH5	NM_172375.3	c.*851C>A		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.2884C>A	p.Pro962Thr	missense_variant	11/11	1	NM_139318.5	ENSP00000321427.7
KCNH5	ENST00000420622	c.*851C>A		3_prime_UTR_variant	10/10	1		ENSP00000395439.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000504 AC: 1 AN: 198396 Hom.: 0 AF XY: 0.00000955 AC XY: 1 AN XY: 104698

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000588

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1382248 Hom.: 0 Cov.: 29 AF XY: 0.00 AC XY: 0 AN XY: 677092

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000827 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.057
BayesDel_addAF	Uncertain	0.095	D
BayesDel_noAF	Uncertain	0.080
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Benign	0.12	T
Eigen	Uncertain	0.42
Eigen_PC	Uncertain	0.51
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Benign	0.78	T
M_CAP	Uncertain	0.10	D
MetaRNN	Benign	0.34	T
MetaSVM	Pathogenic	0.81	D
MutationAssessor	Benign	0.69	N
PrimateAI	Uncertain	0.59	T
PROVEAN	Benign	-0.33	N
REVEL	Uncertain	0.49
Sift	Benign	0.12	T
Sift4G	Benign	0.11	T
Polyphen		1.0	D
Vest4		0.29
MutPred		0.18		Gain of catalytic residue at P966 (P = 0);
MVP		0.42
MPC		0.13
ClinPred		0.53	D
GERP RS		5.4
Varity_R		0.11
gMVP		0.35

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: rs202223175; hg19: chr14-63174309;