rs757467258

Positions:

• chr16-1210779-C-T

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_021098.3(CACNA1H):​c.4039-8C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000131 in 1,599,538 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 34)
  • Exomes 𝑓: 0.000014 (0 hom.)
• Consequence: CACNA1H NM_021098.3 splice_region, intron
• Scores: Splicing: ADA: 0.00002348
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.320

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 Benign. Variant got -16 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 16-1210779-C-T is Benign according to our data. Variant chr16-1210779-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 460107.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAdExome4 at 20 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CACNA1H	NM_021098.3	c.4039-8C>T		splice_region_variant, intron_variant		ENST00000348261.11	NP_066921.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CACNA1H	ENST00000348261.11	c.4039-8C>T		splice_region_variant, intron_variant		1	NM_021098.3	ENSP00000334198.7
CACNA1H	ENST00000565831.6	c.4039-8C>T		splice_region_variant, intron_variant		1		ENSP00000455840.1
CACNA1H	ENST00000638323.1	c.4000-8C>T		splice_region_variant, intron_variant		5		ENSP00000492267.1
CACNA1H	ENST00000569107.5	c.262-8C>T		splice_region_variant, intron_variant		1		ENSP00000454990.2
CACNA1H	ENST00000564231.5	c.262-8C>T		splice_region_variant, intron_variant		1		ENSP00000457555.2
CACNA1H	ENST00000562079.5	c.262-8C>T		splice_region_variant, intron_variant		1		ENSP00000454581.2
CACNA1H	ENST00000637236.2	n.*9-8C>T		splice_region_variant, intron_variant		5		ENSP00000492650.2
CACNA1H	ENST00000639478.1	n.4039-8C>T		splice_region_variant, intron_variant		5		ENSP00000491945.1
CACNA1H	ENST00000640028.1	n.*1952-8C>T		splice_region_variant, intron_variant		5		ENSP00000491488.1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152264 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000466 AC: 11 AN: 235902 Hom.: 0 AF XY: 0.0000540 AC XY: 7 AN XY: 129640

Gnomad AFR exome AF: 0.0000666

Gnomad AMR exome AF: 0.0000582

Gnomad ASJ exome AF: 0.000202

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000274

Gnomad OTH exome AF: 0.000509

GnomAD4 exome AF: 0.0000138 AC: 20 AN: 1447274 Hom.: 0 Cov.: 39 AF XY: 0.0000125 AC XY: 9 AN XY: 720444

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000448

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000900

Gnomad4 OTH exome AF: 0.000116

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152264 Hom.: 0 Cov.: 34 AF XY: 0.00 AC XY: 0 AN XY: 74388

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000480 Hom.: 0

Bravo AF: 0.0000113

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Idiopathic generalized epilepsy;C4310756:Hyperaldosteronism, familial, type IV Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Aug 31, 2023

- -

not provided Benign:1

Likely benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.73
DANN	Benign	0.43

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000023
dbscSNV1_RF	Benign	0.018
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs757467258; hg19: chr16-1260779;