14-62950126-T-G

Variant names:

• chr14-62950126-T-G
• rs79489451
• NM_139318.5:c.1369+7A>C

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_139318.5(KCNH5):​c.1369+7A>C variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,460,030 control chromosomes in the GnomAD database, with no homozygous occurrence. 3/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: KCNH5 NM_139318.5 splice_region, intron
• Scores: Splicing: ADA: 0.02946
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.66
• Publications: 0 publications found

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]

KCNH5 Gene-Disease associations (from GenCC):

• infantile-onset epilepsy

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• developmental and epileptic encephalopathy 112

  Inheritance: AD Classification: STRONG Submitted by: G2P

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

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

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_139318.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCNH5	NM_139318.5	MANE Select	c.1369+7A>C		splice_region intron	N/A	NP_647479.2
	KCNH5	NM_172375.3		c.1369+7A>C		splice_region intron	N/A	NP_758963.1	Q8NCM2-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCNH5	ENST00000322893.12	TSL:1 MANE Select	c.1369+7A>C		splice_region intron	N/A	ENSP00000321427.7	Q8NCM2-1
	KCNH5	ENST00000420622.6	TSL:1	c.1369+7A>C		splice_region intron	N/A	ENSP00000395439.2	Q8NCM2-2
	KCNH5	ENST00000394964.3	TSL:1	n.1541A>C		non_coding_transcript_exon	Exon 7 of 7

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460030 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 726332

African (AFR) AF: 0.00 AC: 0 AN: 33382

American (AMR) AF: 0.00 AC: 0 AN: 44520

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26090

East Asian (EAS) AF: 0.00 AC: 0 AN: 39596

South Asian (SAS) AF: 0.00 AC: 0 AN: 85900

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53354

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5758

European-Non Finnish (NFE) AF: 9.00e-7 AC: 1 AN: 1111114

Other (OTH) AF: 0.00 AC: 0 AN: 60316

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.33
CADD	Benign	15
DANN	Benign	0.95
PhyloP100		2.7

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.029
dbscSNV1_RF	Benign	0.092
SpliceAI score (max)		0.11		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs79489451; hg19: chr14-63416844;