rs60415676

chr16-1201929-T-C

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.1479T>C(p.Ser493=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000779 in 1,549,862 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0040 (4 hom., cov: 34)
  • Exomes 𝑓: 0.00043 (2 hom.)
• Consequence: CACNA1H NM_021098.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.430

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=-0.93).
• BP6: Variant 16-1201929-T-C is Benign according to our data. Variant chr16-1201929-T-C is described in ClinVar as [Benign]. Clinvar id is 460046.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.43 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00395 (602/152326) while in subpopulation AFR AF= 0.014 (583/41582). AF 95% confidence interval is 0.0131. There are 4 homozygotes in gnomad4. There are 266 alleles in male gnomad4 subpopulation. Median coverage is 34. This position pass quality control queck.
• BS2: High AC in GnomAd at 601 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CACNA1H	NM_021098.3	c.1479T>C	p.Ser493=	synonymous_variant	9/35	ENST00000348261.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CACNA1H	ENST00000348261.11	c.1479T>C	p.Ser493=	synonymous_variant	9/35	1	NM_021098.3	P4

Frequencies

GnomAD3 genomes AF: 0.00395 AC: 601 AN: 152208 Hom.: 4 Cov.: 34

Gnomad AFR AF: 0.0140

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

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: 0.000132

Gnomad OTH AF: 0.00287

GnomAD3 exomes AF: 0.000817 AC: 121 AN: 148134 Hom.: 0 AF XY: 0.000541 AC XY: 43 AN XY: 79446

Gnomad AFR exome AF: 0.0146

Gnomad AMR exome AF: 0.000366

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000441

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000906

Gnomad OTH exome AF: 0.000467

GnomAD4 exome AF: 0.000433 AC: 605 AN: 1397536 Hom.: 2 Cov.: 36 AF XY: 0.000383 AC XY: 264 AN XY: 689274

Gnomad4 AFR exome AF: 0.0147

Gnomad4 AMR exome AF: 0.000700

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000379

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000454

Gnomad4 OTH exome AF: 0.000932

GnomAD4 genome AF: 0.00395 AC: 602 AN: 152326 Hom.: 4 Cov.: 34 AF XY: 0.00357 AC XY: 266 AN XY: 74486

Gnomad4 AFR AF: 0.0140

Gnomad4 AMR AF: 0.000261

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000132

Gnomad4 OTH AF: 0.00284

Alfa AF: 0.00116 Hom.: 1

Bravo AF: 0.00445

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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

Benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Sep 06, 2021

- -

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

Benign, criteria provided, single submitter

clinical testing

Invitae

Dec 12, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
Cadd	Benign	0.91
Dann	Benign	0.37

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: rs60415676; hg19: chr16-1251929;