14-62981225-G-T

Variant names:

• chr14-62981225-G-T
• NM_139318.5:c.589C>A

Variant summary

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

The NM_139318.5(KCNH5):​c.589C>A​(p.Gln197Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,766 control chromosomes in the GnomAD database, with no homozygous occurrence. 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
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 9.93

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.589C>A	p.Gln197Lys	missense_variant	Exon 6 of 11	ENST00000322893.12	NP_647479.2
KCNH5	NM_172375.3	c.589C>A	p.Gln197Lys	missense_variant	Exon 6 of 10		NP_758963.1
KCNH5	XM_047431275.1	c.589C>A	p.Gln197Lys	missense_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.589C>A	p.Gln197Lys	missense_variant	Exon 6 of 11	1	NM_139318.5	ENSP00000321427.7
KCNH5	ENST00000420622.6	c.589C>A	p.Gln197Lys	missense_variant	Exon 6 of 10	1		ENSP00000395439.2
KCNH5	ENST00000394964.3	n.754C>A		non_coding_transcript_exon_variant	Exon 6 of 7	1
KCNH5	ENST00000394968.2	c.415C>A	p.Gln139Lys	missense_variant	Exon 6 of 11	2		ENSP00000378419.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461766 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727190

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	Pathogenic	0.68
BayesDel_addAF	Pathogenic	0.36	D
BayesDel_noAF	Pathogenic	0.28
CADD	Pathogenic	31
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.56	D;.;.
Eigen	Uncertain	0.63
Eigen_PC	Pathogenic	0.67
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.97	D;D;D
M_CAP	Uncertain	0.11	D
MetaRNN	Uncertain	0.64	D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.6	M;M;.
PrimateAI	Pathogenic	0.85	D
PROVEAN	Uncertain	-3.5	D;D;D
REVEL	Pathogenic	0.80
Sift	Benign	0.90	T;T;T
Sift4G	Benign	0.77	T;T;T
Polyphen		0.95	P;P;P
Vest4		0.65
MutPred		0.45		Gain of catalytic residue at K201 (P = 0.0026);Gain of catalytic residue at K201 (P = 0.0026);.;
MVP		0.95
MPC		1.9
ClinPred		0.98	D
GERP RS		5.3
Varity_R		0.74
gMVP		0.62

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

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: chr14-63447943;