rs61073355

chr16-1204272-C-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_021098.3(CACNA1H):c.2265C>T(p.Gly755=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00611 in 1,608,354 control chromosomes in the GnomAD database, including 46 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0047 (3 hom., cov: 33)
  • Exomes 𝑓: 0.0063 (43 hom.)
• Consequence: CACNA1H NM_021098.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.874

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BP6: Variant 16-1204272-C-T is Benign according to our data. Variant chr16-1204272-C-T is described in ClinVar as [Benign]. Clinvar id is 96007.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-1204272-C-T is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=0.874 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00467 (712/152372) while in subpopulation NFE AF= 0.00739 (503/68026). AF 95% confidence interval is 0.00686. There are 3 homozygotes in gnomad4. There are 351 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High AC in GnomAd at 712 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CACNA1H	NM_021098.3	c.2265C>T	p.Gly755=	synonymous_variant	10/35	ENST00000348261.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CACNA1H	ENST00000348261.11	c.2265C>T	p.Gly755=	synonymous_variant	10/35	1	NM_021098.3	P4

Frequencies

GnomAD3 genomes AF: 0.00468 AC: 712 AN: 152254 Hom.: 3 Cov.: 33

Gnomad AFR AF: 0.00123

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00347

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00186

Gnomad FIN AF: 0.00809

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00739

Gnomad OTH AF: 0.00382

GnomAD3 exomes AF: 0.00494 AC: 1158 AN: 234346 Hom.: 5 AF XY: 0.00497 AC XY: 640 AN XY: 128734

Gnomad AFR exome AF: 0.00117

Gnomad AMR exome AF: 0.00205

Gnomad ASJ exome AF: 0.000831

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00324

Gnomad FIN exome AF: 0.00646

Gnomad NFE exome AF: 0.00771

Gnomad OTH exome AF: 0.00605

GnomAD4 exome AF: 0.00626 AC: 9121 AN: 1455982 Hom.: 43 Cov.: 32 AF XY: 0.00619 AC XY: 4484 AN XY: 723850

Gnomad4 AFR exome AF: 0.00102

Gnomad4 AMR exome AF: 0.00224

Gnomad4 ASJ exome AF: 0.00119

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00326

Gnomad4 FIN exome AF: 0.00639

Gnomad4 NFE exome AF: 0.00723

Gnomad4 OTH exome AF: 0.00519

GnomAD4 genome AF: 0.00467 AC: 712 AN: 152372 Hom.: 3 Cov.: 33 AF XY: 0.00471 AC XY: 351 AN XY: 74516

Gnomad4 AFR AF: 0.00123

Gnomad4 AMR AF: 0.00346

Gnomad4 ASJ AF: 0.000576

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00186

Gnomad4 FIN AF: 0.00809

Gnomad4 NFE AF: 0.00739

Gnomad4 OTH AF: 0.00378

Alfa AF: 0.00608 Hom.: 1

Bravo AF: 0.00409

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jun 21, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jul 05, 2013	- -

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

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 25, 2024

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Sep 01, 2022

CACNA1H: BS1, BS2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
Cadd	Benign	3.2
Dann	Benign	0.65

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs61073355; hg19: chr16-1254272;