16-1213775-C-T

Variant names:

• chr16-1213775-C-T
• rs72552061
• NM_021098.3:c.4778-5C>T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_021098.3(CACNA1H):​c.4778-5C>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 0.00132 in 1,547,640 control chromosomes in the GnomAD database, including 2 homozygotes. 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 0.0012 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0013 (1 hom.)
• Consequence: CACNA1H NM_021098.3 splice_region, intron
• Scores: Splicing: ADA: 0.00002190
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -2.22

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BP6: Variant 16-1213775-C-T is Benign according to our data. Variant chr16-1213775-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 460125.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-1213775-C-T is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00125 (190/152048) while in subpopulation AMR AF= 0.00274 (42/15308). AF 95% confidence interval is 0.00209. There are 1 homozygotes in gnomad4. There are 87 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 190 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1H	NM_021098.3	c.4778-5C>T		splice_region_variant, intron_variant	Intron 26 of 34	ENST00000348261.11	NP_066921.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CACNA1H	ENST00000348261.11	c.4778-5C>T		splice_region_variant, intron_variant	Intron 26 of 34	1	NM_021098.3	ENSP00000334198.7
CACNA1H	ENST00000565831.6	c.4760-5C>T		splice_region_variant, intron_variant	Intron 24 of 32	1		ENSP00000455840.1
CACNA1H	ENST00000638323.1	c.4739-5C>T		splice_region_variant, intron_variant	Intron 26 of 34	5		ENSP00000492267.1
CACNA1H	ENST00000569107.5	c.1016-5C>T		splice_region_variant, intron_variant	Intron 8 of 16	1		ENSP00000454990.2
CACNA1H	ENST00000564231.5	c.1001-5C>T		splice_region_variant, intron_variant	Intron 9 of 17	1		ENSP00000457555.2
CACNA1H	ENST00000562079.5	c.983-5C>T		splice_region_variant, intron_variant	Intron 8 of 16	1		ENSP00000454581.2
CACNA1H	ENST00000639478.1	n.4716-5C>T		splice_region_variant, intron_variant	Intron 26 of 34	5		ENSP00000491945.1
CACNA1H	ENST00000640028.1	n.*2629-5C>T		splice_region_variant, intron_variant	Intron 26 of 34	5		ENSP00000491488.1

Frequencies

GnomAD3 genomes AF: 0.00125 AC: 190 AN: 151930 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000556

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00275

Gnomad ASJ AF: 0.00519

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00149

Gnomad OTH AF: 0.00287

GnomAD3 exomes AF: 0.00143 AC: 223 AN: 155958 Hom.: 0 AF XY: 0.00133 AC XY: 111 AN XY: 83750

Gnomad AFR exome AF: 0.000237

Gnomad AMR exome AF: 0.00184

Gnomad ASJ exome AF: 0.00726

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000884

Gnomad NFE exome AF: 0.00158

Gnomad OTH exome AF: 0.00268

GnomAD4 exome AF: 0.00133 AC: 1852 AN: 1395592 Hom.: 1 Cov.: 31 AF XY: 0.00130 AC XY: 897 AN XY: 688868

Gnomad4 AFR exome AF: 0.000220

Gnomad4 AMR exome AF: 0.00217

Gnomad4 ASJ exome AF: 0.00635

Gnomad4 EAS exome AF: 0.0000552

Gnomad4 SAS exome AF: 0.0000126

Gnomad4 FIN exome AF: 0.0000473

Gnomad4 NFE exome AF: 0.00140

Gnomad4 OTH exome AF: 0.00150

GnomAD4 genome AF: 0.00125 AC: 190 AN: 152048 Hom.: 1 Cov.: 32 AF XY: 0.00117 AC XY: 87 AN XY: 74330

Gnomad4 AFR AF: 0.000554

Gnomad4 AMR AF: 0.00274

Gnomad4 ASJ AF: 0.00519

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00149

Gnomad4 OTH AF: 0.00284

Alfa AF: 0.00175 Hom.: 0

Bravo AF: 0.00156

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Apr 11, 2018

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 17, 2021

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

CACNA1H: BS1, BS2 -

CACNA1H-related disorder Benign:1

Mar 30, 2021

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

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

Jan 22, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	0.77
DANN	Benign	0.95

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000022
dbscSNV1_RF	Benign	0.0020
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: rs72552061; hg19: chr16-1263775; COSMIC: COSV61998054; COSMIC: COSV61998054;