14-62981264-C-A

Variant names:

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

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_139318.5(KCNH5):​c.550G>T​(p.Val184Phe) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,408 control chromosomes in the GnomAD database, with no homozygous occurrence. 2/3 splice prediction tools predicting alterations to normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: KCNH5 NM_139318.5 missense, splice_region
• Scores: Splicing: ADA: 0.9993
• Clinical Significance: Not reported in ClinVar
• 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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNH5	NM_139318.5	c.550G>T	p.Val184Phe	missense_variant, splice_region_variant	Exon 6 of 11	ENST00000322893.12	NP_647479.2
KCNH5	NM_172375.3	c.550G>T	p.Val184Phe	missense_variant, splice_region_variant	Exon 6 of 10		NP_758963.1
KCNH5	XM_047431275.1	c.550G>T	p.Val184Phe	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>T	p.Val184Phe	missense_variant, splice_region_variant	Exon 6 of 11	1	NM_139318.5	ENSP00000321427.7
KCNH5	ENST00000420622.6	c.550G>T	p.Val184Phe	missense_variant, splice_region_variant	Exon 6 of 10	1		ENSP00000395439.2
KCNH5	ENST00000394964.3	n.715G>T		splice_region_variant, non_coding_transcript_exon_variant	Exon 6 of 7	1
KCNH5	ENST00000394968.2	c.376G>T	p.Val126Phe	missense_variant, splice_region_variant	Exon 6 of 11	2		ENSP00000378419.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461408 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727038

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: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.49
BayesDel_addAF	Pathogenic	0.48	D
BayesDel_noAF	Pathogenic	0.45
CADD	Pathogenic	34
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.59	D;.;.
Eigen	Uncertain	0.52
Eigen_PC	Uncertain	0.58
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.96	D;D;D
M_CAP	Uncertain	0.26	D
MetaRNN	Uncertain	0.56	D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.2	M;M;.
PrimateAI	Uncertain	0.77	T
PROVEAN	Uncertain	-2.5	N;N;D
REVEL	Pathogenic	0.83
Sift	Uncertain	0.0010	D;D;D
Sift4G	Uncertain	0.034	D;D;D
Polyphen		0.98	D;P;P
Vest4		0.63
MutPred		0.46		Loss of loop (P = 0.0804);Loss of loop (P = 0.0804);.;
MVP		0.94
MPC		1.6
ClinPred		0.99	D
GERP RS		5.3
Varity_R		0.66
gMVP		0.85

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.94
SpliceAI score (max)		0.34		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.34		Position offset: 0

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr14-63447982;