16-1205206-C-T

Position:

• chr16-1205206-C-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_021098.3(CACNA1H):​c.2544C>T​(p.Gly848Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00986 in 1,613,002 control chromosomes in the GnomAD database, including 1,267 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.051 (661 hom., cov: 33)
  • Exomes 𝑓: 0.0056 (606 hom.)
• Consequence: CACNA1H NM_021098.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -1.44

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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.45).
• BP6: Variant 16-1205206-C-T is Benign according to our data. Variant chr16-1205206-C-T is described in ClinVar as [Benign]. Clinvar id is 460066.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.44 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.172 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CACNA1H	NM_021098.3	c.2544C>T	p.Gly848Gly	synonymous_variant	11/35	ENST00000348261.11	NP_066921.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CACNA1H	ENST00000348261.11	c.2544C>T	p.Gly848Gly	synonymous_variant	11/35	1	NM_021098.3	ENSP00000334198.7
CACNA1H	ENST00000565831.6	c.2544C>T	p.Gly848Gly	synonymous_variant	10/33	1		ENSP00000455840.1
CACNA1H	ENST00000638323.1	c.2505C>T	p.Gly835Gly	synonymous_variant	11/35	5		ENSP00000492267.1
CACNA1H	ENST00000639478.1	n.2544C>T		non_coding_transcript_exon_variant	11/35	5		ENSP00000491945.1
CACNA1H	ENST00000640028.1	n.*457C>T		non_coding_transcript_exon_variant	11/35	5		ENSP00000491488.1
CACNA1H	ENST00000640028.1	n.*457C>T		3_prime_UTR_variant	11/35	5		ENSP00000491488.1

Frequencies

GnomAD3 genomes AF: 0.0508 AC: 7733 AN: 152156 Hom.: 650 Cov.: 33

Gnomad AFR AF: 0.175

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0228

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000413

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.00100

Gnomad OTH AF: 0.0363

GnomAD3 exomes AF: 0.0133 AC: 3299 AN: 248584 Hom.: 248 AF XY: 0.0101 AC XY: 1365 AN XY: 135094

Gnomad AFR exome AF: 0.180

Gnomad AMR exome AF: 0.0106

Gnomad ASJ exome AF: 0.000998

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000523

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000746

Gnomad OTH exome AF: 0.00779

GnomAD4 exome AF: 0.00557 AC: 8131 AN: 1460728 Hom.: 606 Cov.: 32 AF XY: 0.00486 AC XY: 3529 AN XY: 726638

Gnomad4 AFR exome AF: 0.181

Gnomad4 AMR exome AF: 0.0119

Gnomad4 ASJ exome AF: 0.00107

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000487

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000511

Gnomad4 OTH exome AF: 0.0134

GnomAD4 genome AF: 0.0511 AC: 7777 AN: 152274 Hom.: 661 Cov.: 33 AF XY: 0.0491 AC XY: 3658 AN XY: 74468

Gnomad4 AFR AF: 0.175

Gnomad4 AMR AF: 0.0228

Gnomad4 ASJ AF: 0.00115

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00100

Gnomad4 OTH AF: 0.0360

Alfa AF: 0.00445 Hom.: 12

Bravo AF: 0.0586

EpiCase AF: 0.00104

EpiControl AF: 0.00131

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 26, 2020	- -

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

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 30, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.45
CADD	Benign	0.92
DANN	Benign	0.74

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: rs28365123; hg19: chr16-1255206;