chr16-1220055-T-A

Variant names:

• chr16-1220055-T-A
• rs3751889
• NM_021098.3:c.6123T>A

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PVS1 PM2

The ENST00000711482.1(CACNA1H):​c.6121+2T>A variant causes a splice donor, intron change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 1/1 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: 34)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: CACNA1H ENST00000711482.1 splice_donor, intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -3.98
• Publications: 11 publications found

Genes affected

CACNA1H (HGNC:1395): (calcium voltage-gated channel subunit alpha1 H) This gene encodes a T-type member of the alpha-1 subunit family, a protein in the voltage-dependent calcium channel complex. Calcium channels mediate the influx of calcium ions into the cell upon membrane polarization and consist of a complex of alpha-1, alpha-2/delta, beta, and gamma subunits in a 1:1:1:1 ratio. The alpha-1 subunit has 24 transmembrane segments and forms the pore through which ions pass into the cell. There are multiple isoforms of each of the proteins in the complex, either encoded by different genes or the result of alternative splicing of transcripts. Alternate transcriptional splice variants, encoding different isoforms, have been characterized for the gene described here. Studies suggest certain mutations in this gene lead to childhood absence epilepsy (CAE). [provided by RefSeq, Jul 2008]

CACNA1H Gene-Disease associations (from GenCC):

• hyperaldosteronism, familial, type IV

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• childhood absence epilepsy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• epilepsy, childhood absence, susceptibility to, 6

  Inheritance: AD Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae), G2P
• epilepsy

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Pathogenic. The variant received 10 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, Cryptic splice site detected, with MaxEntScore 9.4, offset of 14, new splice context is: ccgGTgagg. Cryptic site results in frameshift change. If cryptic site found is not functional and variant results in exon loss, it results in frameshift change.
• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000711482.1. 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
	CACNA1H	NM_021098.3	MANE Select	c.6123T>A	p.Gly2041Gly	synonymous	Exon 35 of 35	NP_066921.2	O95180-1
	CACNA1H	NM_001005407.2		c.6105T>A	p.Gly2035Gly	synonymous	Exon 34 of 34	NP_001005407.1	O95180-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CACNA1H	ENST00000348261.11	TSL:1 MANE Select	c.6123T>A	p.Gly2041Gly	synonymous	Exon 35 of 35	ENSP00000334198.7	O95180-1
	CACNA1H	ENST00000569107.6	TSL:1	c.6138T>A	p.Gly2046Gly	synonymous	Exon 34 of 34	ENSP00000454990.2	H3BNT0
	CACNA1H	ENST00000711493.1		c.6108T>A	p.Gly2036Gly	synonymous	Exon 34 of 34	ENSP00000518778.1	A0AAA9YHG8

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1275028 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 618342

African (AFR) AF: 0.00 AC: 0 AN: 25374

American (AMR) AF: 0.00 AC: 0 AN: 19692

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 17826

East Asian (EAS) AF: 0.00 AC: 0 AN: 30946

South Asian (SAS) AF: 0.00 AC: 0 AN: 54094

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 45862

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5116

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1023594

Other (OTH) AF: 0.00 AC: 0 AN: 52524

GnomAD4 genome Cov.: 34

Alfa AF: 0.00 Hom.: 153

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.027
DANN	Benign	0.51
PhyloP100		-4.0

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

Other links and lift over

dbSNP: rs3751889; hg19: chr16-1270055;