19-13207858-CCTGCTGCTGCTGCTGCTGCTGCTGCTGCTG-CCTGCTGCTGCTGCTGCTGCTG

Variant names:

• chr19-13207858-CCTGCTGCTG-C
• rs16054
• NM_001127222.2:c.6967_6975delCAGCAGCAG

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP6_Moderate BS1 BS2

The NM_001127222.2(CACNA1A):​c.6967_6975delCAGCAGCAG​(p.Gln2323_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 0.00275 in 1,370,548 control chromosomes in the GnomAD database, including 7 homozygotes. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0033 (3 hom., cov: 0)
  • Exomes 𝑓: 0.0027 (4 hom.)
• Consequence: CACNA1A NM_001127222.2 conservative_inframe_deletion
• Clinical Significance: Likely benign criteria provided, single submitter B:2
• Conservation: PhyloP100: 0.785

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 -10 ACMG points.

• BP6: Variant 19-13207858-CCTGCTGCTG-C is Benign according to our data. Variant chr19-13207858-CCTGCTGCTG-C is described in ClinVar as [Likely_benign]. Clinvar id is 2578818.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr19-13207858-CCTGCTGCTG-C is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00325 (481/147858) while in subpopulation AFR AF= 0.00963 (387/40188). AF 95% confidence interval is 0.00884. There are 3 homozygotes in gnomad4. There are 226 alleles in male gnomad4 subpopulation. Median coverage is 0. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 481 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1A	NM_001127222.2	c.6967_6975delCAGCAGCAG	p.Gln2323_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.6967_6975delCAGCAGCAG	p.Gln2323_Gln2325del	conservative_inframe_deletion	Exon 47 of 47	1	NM_001127222.2	ENSP00000353362.5
CACNA1A	ENST00000638029.1	c.6985_6993delCAGCAGCAG	p.Gln2329_Gln2331del	conservative_inframe_deletion	Exon 48 of 48	5		ENSP00000489829.1
CACNA1A	ENST00000573710.7	c.6973_6981delCAGCAGCAG	p.Gln2325_Gln2327del	conservative_inframe_deletion	Exon 47 of 47	5		ENSP00000460092.3
CACNA1A	ENST00000635727.1	c.6970_6978delCAGCAGCAG	p.Gln2324_Gln2326del	conservative_inframe_deletion	Exon 47 of 47	5		ENSP00000490001.1
CACNA1A	ENST00000637769.1	c.6970_6978delCAGCAGCAG	p.Gln2324_Gln2326del	conservative_inframe_deletion	Exon 47 of 47	1		ENSP00000489778.1
CACNA1A	ENST00000636012.1	c.6934_6942delCAGCAGCAG	p.Gln2312_Gln2314del	conservative_inframe_deletion	Exon 46 of 46	5		ENSP00000490223.1
CACNA1A	ENST00000637736.1	c.6829_6837delCAGCAGCAG	p.Gln2277_Gln2279del	conservative_inframe_deletion	Exon 46 of 46	5		ENSP00000489861.1
CACNA1A	ENST00000636389	c.*53_*61delCAGCAGCAG		3_prime_UTR_variant	Exon 47 of 47	5		ENSP00000489992.1
CACNA1A	ENST00000637432	c.*179_*187delCAGCAGCAG		3_prime_UTR_variant	Exon 48 of 48	5		ENSP00000490617.1
CACNA1A	ENST00000635895	c.*179_*187delCAGCAGCAG		3_prime_UTR_variant	Exon 47 of 47	5		ENSP00000490323.1
CACNA1A	ENST00000638009	c.*179_*187delCAGCAGCAG		3_prime_UTR_variant	Exon 47 of 47	1		ENSP00000489913.1
CACNA1A	ENST00000637276	c.*179_*187delCAGCAGCAG		3_prime_UTR_variant	Exon 46 of 46	5		ENSP00000489777.1
CACNA1A	ENST00000636549.1	c.*179_*187delCAGCAGCAG		downstream_gene_variant		5		ENSP00000490578.1
CACNA1A	ENST00000637927.1	c.*179_*187delCAGCAGCAG		downstream_gene_variant		5		ENSP00000489715.1

Frequencies

GnomAD3 genomes AF: 0.00324 AC: 478 AN: 147756 Hom.: 3 Cov.: 0

Gnomad AFR AF: 0.00961

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00134

Gnomad ASJ AF: 0.00378

Gnomad EAS AF: 0.00207

Gnomad SAS AF: 0.00149

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000586

Gnomad OTH AF: 0.00198

GnomAD3 exomes AF: 0.00563 AC: 293 AN: 52038 Hom.: 1 AF XY: 0.00609 AC XY: 182 AN XY: 29882

Gnomad AFR exome AF: 0.0146

Gnomad AMR exome AF: 0.00657

Gnomad ASJ exome AF: 0.0103

Gnomad EAS exome AF: 0.00114

Gnomad SAS exome AF: 0.00777

Gnomad FIN exome AF: 0.00211

Gnomad NFE exome AF: 0.00431

Gnomad OTH exome AF: 0.00329

GnomAD4 exome AF: 0.00269 AC: 3293 AN: 1222690 Hom.: 4 AF XY: 0.00289 AC XY: 1735 AN XY: 601300

Gnomad4 AFR exome AF: 0.0146

Gnomad4 AMR exome AF: 0.00838

Gnomad4 ASJ exome AF: 0.00729

Gnomad4 EAS exome AF: 0.00184

Gnomad4 SAS exome AF: 0.00810

Gnomad4 FIN exome AF: 0.00188

Gnomad4 NFE exome AF: 0.00185

Gnomad4 OTH exome AF: 0.00378

GnomAD4 genome AF: 0.00325 AC: 481 AN: 147858 Hom.: 3 Cov.: 0 AF XY: 0.00314 AC XY: 226 AN XY: 71970

Gnomad4 AFR AF: 0.00963

Gnomad4 AMR AF: 0.00134

Gnomad4 ASJ AF: 0.00378

Gnomad4 EAS AF: 0.00208

Gnomad4 SAS AF: 0.00149

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000586

Gnomad4 OTH AF: 0.00196

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Aug 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

CACNA1A: PM4, BS1, BS2 -

CACNA1A-related disorder Benign:1

Sep 30, 2019

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Splicing

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;