rs201309183

Positions:

• chr16-1213862-C-T

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 0P and 11B. BP4_Strong BP6_Moderate BP7 BS2

The NM_021098.3(CACNA1H):​c.4860C>T​(p.Asp1620Asp) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000228 in 1,610,388 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.00021 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00023 (2 hom.)
• Consequence: CACNA1H NM_021098.3 synonymous
• Clinical Significance: Likely benign criteria provided, single submitter B:2
• Conservation: PhyloP100: 0.0460

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 -11 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.58).
• BP6: Variant 16-1213862-C-T is Benign according to our data. Variant chr16-1213862-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 460129.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=0.046 with no splicing effect.
• BS2: High AC in GnomAd4 at 32 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CACNA1H	NM_021098.3	c.4860C>T	p.Asp1620Asp	synonymous_variant	27/35	ENST00000348261.11	NP_066921.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CACNA1H	ENST00000348261.11	c.4860C>T	p.Asp1620Asp	synonymous_variant	27/35	1	NM_021098.3	ENSP00000334198.7
CACNA1H	ENST00000565831.6	c.4842C>T	p.Asp1614Asp	synonymous_variant	25/33	1		ENSP00000455840.1
CACNA1H	ENST00000638323.1	c.4821C>T	p.Asp1607Asp	synonymous_variant	27/35	5		ENSP00000492267.1
CACNA1H	ENST00000569107.5	c.1098C>T	p.Asp366Asp	synonymous_variant	9/17	1		ENSP00000454990.2
CACNA1H	ENST00000564231.5	c.1083C>T	p.Asp361Asp	synonymous_variant	10/18	1		ENSP00000457555.2
CACNA1H	ENST00000562079.5	c.1065C>T	p.Asp355Asp	synonymous_variant	9/17	1		ENSP00000454581.2
CACNA1H	ENST00000639478.1	n.4798C>T		non_coding_transcript_exon_variant	27/35	5		ENSP00000491945.1
CACNA1H	ENST00000640028.1	n.*2711C>T		non_coding_transcript_exon_variant	27/35	5		ENSP00000491488.1
CACNA1H	ENST00000640028.1	n.*2711C>T		3_prime_UTR_variant	27/35	5		ENSP00000491488.1

Frequencies

GnomAD3 genomes AF: 0.000204 AC: 31 AN: 152168 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000482

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.0000941

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000323

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000268 AC: 65 AN: 242918 Hom.: 0 AF XY: 0.000235 AC XY: 31 AN XY: 132196

Gnomad AFR exome AF: 0.000137

Gnomad AMR exome AF: 0.0000294

Gnomad ASJ exome AF: 0.000101

Gnomad EAS exome AF: 0.000564

Gnomad SAS exome AF: 0.000269

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000382

Gnomad OTH exome AF: 0.000169

GnomAD4 exome AF: 0.000230 AC: 335 AN: 1458102 Hom.: 2 Cov.: 31 AF XY: 0.000233 AC XY: 169 AN XY: 724968

Gnomad4 AFR exome AF: 0.000120

Gnomad4 AMR exome AF: 0.000226

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000152

Gnomad4 SAS exome AF: 0.000281

Gnomad4 FIN exome AF: 0.0000572

Gnomad4 NFE exome AF: 0.000245

Gnomad4 OTH exome AF: 0.000265

GnomAD4 genome AF: 0.000210 AC: 32 AN: 152286 Hom.: 0 Cov.: 33 AF XY: 0.000242 AC XY: 18 AN XY: 74474

Gnomad4 AFR AF: 0.0000481

Gnomad4 AMR AF: 0.000261

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000622

Gnomad4 FIN AF: 0.0000941

Gnomad4 NFE AF: 0.000323

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000379 Hom.: 0

Bravo AF: 0.000166

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, single submitter

Submissions by phenotype

CACNA1H-related disorder Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 28, 2019

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

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 21, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.58
CADD	Benign	0.24
DANN	Benign	0.68

Splicing

Name	Calibrated prediction	Score	Prediction
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: rs201309183; hg19: chr16-1263862;