chr19-13207858-CCTG-C

Variant names:

• chr19-13207858-CCTG-C
• rs16054
• NM_001127222.2:c.6973_6975delCAG

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_001127222.2(CACNA1A):​c.6973_6975delCAG​(p.Gln2325del) variant causes a conservative inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.176 in 1,245,812 control chromosomes in the GnomAD database, including 8,550 homozygotes. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.20 (3061 hom., cov: 0)
  • Exomes 𝑓: 0.18 (8550 hom.)
  • Failed GnomAD Quality Control
• Consequence: CACNA1A NM_001127222.2 conservative_inframe_deletion
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.00

Genes affected

CACNA1A (HGNC:1388): (calcium voltage-gated channel subunit alpha1 A) Voltage-dependent calcium channels mediate the entry of calcium ions into excitable cells, and are also involved in a variety of calcium-dependent processes, including muscle contraction, hormone or neurotransmitter release, and gene expression. Calcium channels are multisubunit complexes composed of alpha-1, beta, alpha-2/delta, and gamma subunits. The channel activity is directed by the pore-forming alpha-1 subunit, whereas, the others act as auxiliary subunits regulating this activity. The distinctive properties of the calcium channel types are related primarily to the expression of a variety of alpha-1 isoforms, alpha-1A, B, C, D, E, and S. This gene encodes the alpha-1A subunit, which is predominantly expressed in neuronal tissue. Mutations in this gene are associated with 2 neurologic disorders, familial hemiplegic migraine and episodic ataxia 2. This gene also exhibits polymorphic variation due to (CAG)n-repeats. Multiple transcript variants encoding different isoforms have been found for this gene. In one set of transcript variants, the (CAG)n-repeats occur in the 3' UTR, and are not associated with any disease. But in another set of variants, an insertion extends the coding region to include the (CAG)n-repeats which encode a polyglutamine tract. Expansion of the (CAG)n-repeats from the normal 4-18 to 21-33 in the coding region is associated with spinocerebellar ataxia 6. [provided by RefSeq, Jul 2016]

ACMG classification

Verdict is Benign. Variant got -16 ACMG points.

• BP6: Variant 19-13207858-CCTG-C is Benign according to our data. Variant chr19-13207858-CCTG-C is described in ClinVar as [Benign]. Clinvar id is 1295862.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-13207858-CCTG-C is described in Lovd as [Benign]. Variant chr19-13207858-CCTG-C is described in Lovd as [Benign]. Variant chr19-13207858-CCTG-C is described in Lovd as [Likely_benign]. Variant chr19-13207858-CCTG-C is described in Lovd as [Likely_benign].
• BA1: GnomAdExome4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.244 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1A	NM_001127222.2	c.6973_6975delCAG	p.Gln2325del	conservative_inframe_deletion	Exon 47 of 47	ENST00000360228.11	NP_001120694.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CACNA1A	ENST00000360228.11	c.6973_6975delCAG	p.Gln2325del	conservative_inframe_deletion	Exon 47 of 47	1	NM_001127222.2	ENSP00000353362.5
CACNA1A	ENST00000638029.1	c.6991_6993delCAG	p.Gln2331del	conservative_inframe_deletion	Exon 48 of 48	5		ENSP00000489829.1
CACNA1A	ENST00000573710.7	c.6979_6981delCAG	p.Gln2327del	conservative_inframe_deletion	Exon 47 of 47	5		ENSP00000460092.3
CACNA1A	ENST00000635727.1	c.6976_6978delCAG	p.Gln2326del	conservative_inframe_deletion	Exon 47 of 47	5		ENSP00000490001.1
CACNA1A	ENST00000637769.1	c.6976_6978delCAG	p.Gln2326del	conservative_inframe_deletion	Exon 47 of 47	1		ENSP00000489778.1
CACNA1A	ENST00000636012.1	c.6940_6942delCAG	p.Gln2314del	conservative_inframe_deletion	Exon 46 of 46	5		ENSP00000490223.1
CACNA1A	ENST00000637736.1	c.6835_6837delCAG	p.Gln2279del	conservative_inframe_deletion	Exon 46 of 46	5		ENSP00000489861.1
CACNA1A	ENST00000636389	c.*59_*61delCAG		3_prime_UTR_variant	Exon 47 of 47	5		ENSP00000489992.1
CACNA1A	ENST00000637432	c.*185_*187delCAG		3_prime_UTR_variant	Exon 48 of 48	5		ENSP00000490617.1
CACNA1A	ENST00000635895	c.*185_*187delCAG		3_prime_UTR_variant	Exon 47 of 47	5		ENSP00000490323.1
CACNA1A	ENST00000638009	c.*185_*187delCAG		3_prime_UTR_variant	Exon 47 of 47	1		ENSP00000489913.1
CACNA1A	ENST00000637276	c.*185_*187delCAG		3_prime_UTR_variant	Exon 46 of 46	5		ENSP00000489777.1
CACNA1A	ENST00000636549.1	c.*185_*187delCAG		downstream_gene_variant		5		ENSP00000490578.1
CACNA1A	ENST00000637927.1	c.*185_*187delCAG		downstream_gene_variant		5		ENSP00000489715.1

Frequencies

GnomAD3 genomes AF: 0.195 AC: 28780 AN: 147582 Hom.: 3053 Cov.: 0

Gnomad AFR AF: 0.256

Gnomad AMI AF: 0.258

Gnomad AMR AF: 0.116

Gnomad ASJ AF: 0.145

Gnomad EAS AF: 0.0863

Gnomad SAS AF: 0.107

Gnomad FIN AF: 0.272

Gnomad MID AF: 0.0800

Gnomad NFE AF: 0.182

Gnomad OTH AF: 0.145

GnomAD3 exomes AF: 0.186 AC: 9667 AN: 52038 Hom.: 1033 AF XY: 0.183 AC XY: 5478 AN XY: 29882

Gnomad AFR exome AF: 0.310

Gnomad AMR exome AF: 0.118

Gnomad ASJ exome AF: 0.187

Gnomad EAS exome AF: 0.130

Gnomad SAS exome AF: 0.144

Gnomad FIN exome AF: 0.321

Gnomad NFE exome AF: 0.218

Gnomad OTH exome AF: 0.182

GnomAD4 exome AF: 0.176 AC: 219076 AN: 1245812 Hom.: 8550 AF XY: 0.174 AC XY: 106708 AN XY: 612300

Gnomad4 AFR exome AF: 0.249

Gnomad4 AMR exome AF: 0.0912

Gnomad4 ASJ exome AF: 0.146

Gnomad4 EAS exome AF: 0.0983

Gnomad4 SAS exome AF: 0.110

Gnomad4 FIN exome AF: 0.255

Gnomad4 NFE exome AF: 0.181

Gnomad4 OTH exome AF: 0.164

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.195 AC: 28817 AN: 147684 Hom.: 3061 Cov.: 0 AF XY: 0.196 AC XY: 14097 AN XY: 71888

Gnomad4 AFR AF: 0.257

Gnomad4 AMR AF: 0.116

Gnomad4 ASJ AF: 0.145

Gnomad4 EAS AF: 0.0864

Gnomad4 SAS AF: 0.106

Gnomad4 FIN AF: 0.272

Gnomad4 NFE AF: 0.182

Gnomad4 OTH AF: 0.144

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Spinocerebellar ataxia type 6 Benign:1

May 04, 2023

Molecular Genetics, Royal Melbourne Hospital

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

African/African American population allele frequency is 27.41% (rs753460234, 2255/8580 alleles, 311 homozygotes in gnomAD v2.1). Based on the classification scheme RMH Modified ACMG/AMP Guidelines v1.2.1, this variant is classified as BENIGN. Following criteria are met: BA1 -

not provided Benign:1

Jun 14, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Spinocerebellar ataxia type 6;C1720416:Episodic ataxia type 2;C1832884:Migraine, familial hemiplegic, 1;C4310716:Developmental and epileptic encephalopathy, 42 Benign:1

Jul 19, 2021

Fulgent Genetics, Fulgent Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

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: rs16054; hg19: chr19-13318672;