rs375725132

Positions:

• chr16-1220652-C-G
• chr16-1220652-C-T

Variant summary

Our verdict is Benign. Variant got -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BP7 BS2

The NM_021098.3(CACNA1H):​c.6720C>G​(p.Ala2240Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000667 in 1,603,948 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.000092 (1 hom., cov: 33)
  • Exomes 𝑓: 0.000064 (0 hom.)
• Consequence: CACNA1H NM_021098.3 synonymous
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -3.19

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 -17 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BP6: Variant 16-1220652-C-G is Benign according to our data. Variant chr16-1220652-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 529647.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-3.19 with no splicing effect.
• BS2: High AC in GnomAd4 at 14 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CACNA1H	NM_021098.3	c.6720C>G	p.Ala2240Ala	synonymous_variant	35/35	ENST00000348261.11	NP_066921.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CACNA1H	ENST00000348261.11	c.6720C>G	p.Ala2240Ala	synonymous_variant	35/35	1	NM_021098.3	ENSP00000334198.7
CACNA1H	ENST00000565831.6	c.6702C>G	p.Ala2234Ala	synonymous_variant	33/33	1		ENSP00000455840.1
CACNA1H	ENST00000638323.1	c.6681C>G	p.Ala2227Ala	synonymous_variant	35/35	5		ENSP00000492267.1
CACNA1H	ENST00000569107.5	c.2958C>G	p.Ala986Ala	synonymous_variant	17/17	1		ENSP00000454990.2
CACNA1H	ENST00000564231.5	c.2910C>G	p.Ala970Ala	synonymous_variant	18/18	1		ENSP00000457555.2
CACNA1H	ENST00000562079.5	c.2892C>G	p.Ala964Ala	synonymous_variant	17/17	1		ENSP00000454581.2
CACNA1H	ENST00000639478.1	n.*1768C>G		non_coding_transcript_exon_variant	35/35	5		ENSP00000491945.1
CACNA1H	ENST00000640028.1	n.*4538C>G		non_coding_transcript_exon_variant	35/35	5		ENSP00000491488.1
CACNA1H	ENST00000639478.1	n.*1768C>G		3_prime_UTR_variant	35/35	5		ENSP00000491945.1
CACNA1H	ENST00000640028.1	n.*4538C>G		3_prime_UTR_variant	35/35	5		ENSP00000491488.1

Frequencies

GnomAD3 genomes AF: 0.0000922 AC: 14 AN: 151776 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.0000484

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00173

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000208

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000442

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000170 AC: 37 AN: 217252 Hom.: 0 AF XY: 0.000183 AC XY: 22 AN XY: 120072

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000189

Gnomad ASJ exome AF: 0.00253

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000694

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000530

Gnomad OTH exome AF: 0.000184

GnomAD4 exome AF: 0.0000640 AC: 93 AN: 1452054 Hom.: 0 Cov.: 35 AF XY: 0.0000637 AC XY: 46 AN XY: 721720

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000230

Gnomad4 ASJ exome AF: 0.00201

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000350

Gnomad4 FIN exome AF: 0.0000389

Gnomad4 NFE exome AF: 0.00000903

Gnomad4 OTH exome AF: 0.000267

GnomAD4 genome AF: 0.0000922 AC: 14 AN: 151894 Hom.: 1 Cov.: 33 AF XY: 0.0000808 AC XY: 6 AN XY: 74240

Gnomad4 AFR AF: 0.0000483

Gnomad4 AMR AF: 0.0000655

Gnomad4 ASJ AF: 0.00173

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000208

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000442

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000362 Hom.: 0

Bravo AF: 0.000102

ClinVar

Significance: Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

CACNA1H-related disorder Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 22, 2020

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). -

Epilepsy, childhood absence, susceptibility to, 6;C4310756:Hyperaldosteronism, familial, type IV Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Nov 02, 2021

- -

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

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Oct 13, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	0.083
DANN	Benign	0.42

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: rs375725132; hg19: chr16-1270652;