16-1214973-C-A

Position:

• chr16-1214973-C-A

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PVS1 PM2

The NM_021098.3(CACNA1H):​c.4931C>A​(p.Ser1644*) variant causes a stop gained, splice region change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. S1644S) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: CACNA1H NM_021098.3 stop_gained, splice_region
• Scores: Splicing: ADA: 0.9677
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.12

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 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 10 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CACNA1H	NM_021098.3	c.4931C>A	p.Ser1644*	stop_gained, splice_region_variant	28/35	ENST00000348261.11	NP_066921.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CACNA1H	ENST00000348261.11	c.4931C>A	p.Ser1644*	stop_gained, splice_region_variant	28/35	1	NM_021098.3	ENSP00000334198.7
CACNA1H	ENST00000565831.6	c.4913C>A	p.Ser1638*	stop_gained, splice_region_variant	26/33	1		ENSP00000455840.1
CACNA1H	ENST00000638323.1	c.4892C>A	p.Ser1631*	stop_gained, splice_region_variant	28/35	5		ENSP00000492267.1
CACNA1H	ENST00000569107.5	c.1169C>A	p.Ser390*	stop_gained, splice_region_variant	10/17	1		ENSP00000454990.2
CACNA1H	ENST00000564231.5	c.1154C>A	p.Ser385*	stop_gained, splice_region_variant	11/18	1		ENSP00000457555.2
CACNA1H	ENST00000562079.5	c.1136C>A	p.Ser379*	stop_gained, splice_region_variant	10/17	1		ENSP00000454581.2
CACNA1H	ENST00000639478.1	n.*12C>A		splice_region_variant, non_coding_transcript_exon_variant	28/35	5		ENSP00000491945.1
CACNA1H	ENST00000640028.1	n.*2782C>A		splice_region_variant, non_coding_transcript_exon_variant	28/35	5		ENSP00000491488.1
CACNA1H	ENST00000639478.1	n.*12C>A		3_prime_UTR_variant	28/35	5		ENSP00000491945.1
CACNA1H	ENST00000640028.1	n.*2782C>A		3_prime_UTR_variant	28/35	5		ENSP00000491488.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0 AN: 1450418 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 720462

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.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.55	D
BayesDel_noAF	Pathogenic	0.56
CADD	Pathogenic	63
DANN	Uncertain	1.0
Eigen	Pathogenic	0.90
Eigen_PC	Pathogenic	0.71
FATHMM_MKL	Uncertain	0.86	D
Vest4		0.77
GERP RS		4.3

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	0.97
dbscSNV1_RF	Benign	0.68
SpliceAI score (max)		0.97		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.97		Position offset: 2

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

Publications

LitVar

Other links and lift over

dbSNP: rs745902196; hg19: chr16-1264973;