NM_001127222.2:c.6967_6975dupCAGCAGCAG

Variant names:

• chr19-13207858-C-CCTGCTGCTG
• rs16054
• NM_001127222.2:c.6967_6975dupCAGCAGCAG

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP6 BS1 BS2

The NM_001127222.2(CACNA1A):​c.6967_6975dupCAGCAGCAG​(p.Gln2323_Gln2325dup) variant causes a conservative inframe insertion change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00096 (0 hom., cov: 0)
  • Exomes 𝑓: 0.0012 (9 hom.)
• Consequence: CACNA1A NM_001127222.2 conservative_inframe_insertion
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:1
• 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 -9 ACMG points.

• BP6: Variant 19-13207858-C-CCTGCTGCTG is Benign according to our data. Variant chr19-13207858-C-CCTGCTGCTG is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 1711464.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=2}.
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.00096 (142/147902) while in subpopulation EAS AF= 0.0139 (67/4816). AF 95% confidence interval is 0.0112. There are 0 homozygotes in gnomad4. There are 71 alleles in male gnomad4 subpopulation. Median coverage is 0. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 142 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1A	NM_001127222.2	c.6967_6975dupCAGCAGCAG	p.Gln2323_Gln2325dup	conservative_inframe_insertion	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_6975dupCAGCAGCAG	p.Gln2323_Gln2325dup	conservative_inframe_insertion	Exon 47 of 47	1	NM_001127222.2	ENSP00000353362.5
CACNA1A	ENST00000638029.1	c.6985_6993dupCAGCAGCAG	p.Gln2329_Gln2331dup	conservative_inframe_insertion	Exon 48 of 48	5		ENSP00000489829.1
CACNA1A	ENST00000573710.7	c.6973_6981dupCAGCAGCAG	p.Gln2325_Gln2327dup	conservative_inframe_insertion	Exon 47 of 47	5		ENSP00000460092.3
CACNA1A	ENST00000635727.1	c.6970_6978dupCAGCAGCAG	p.Gln2324_Gln2326dup	conservative_inframe_insertion	Exon 47 of 47	5		ENSP00000490001.1
CACNA1A	ENST00000637769.1	c.6970_6978dupCAGCAGCAG	p.Gln2324_Gln2326dup	conservative_inframe_insertion	Exon 47 of 47	1		ENSP00000489778.1
CACNA1A	ENST00000636012.1	c.6934_6942dupCAGCAGCAG	p.Gln2312_Gln2314dup	conservative_inframe_insertion	Exon 46 of 46	5		ENSP00000490223.1
CACNA1A	ENST00000637736.1	c.6829_6837dupCAGCAGCAG	p.Gln2277_Gln2279dup	conservative_inframe_insertion	Exon 46 of 46	5		ENSP00000489861.1
CACNA1A	ENST00000636389	c.*53_*61dupCAGCAGCAG		3_prime_UTR_variant	Exon 47 of 47	5		ENSP00000489992.1
CACNA1A	ENST00000637432	c.*179_*187dupCAGCAGCAG		3_prime_UTR_variant	Exon 48 of 48	5		ENSP00000490617.1
CACNA1A	ENST00000635895	c.*179_*187dupCAGCAGCAG		3_prime_UTR_variant	Exon 47 of 47	5		ENSP00000490323.1
CACNA1A	ENST00000638009	c.*179_*187dupCAGCAGCAG		3_prime_UTR_variant	Exon 47 of 47	1		ENSP00000489913.1
CACNA1A	ENST00000637276	c.*179_*187dupCAGCAGCAG		3_prime_UTR_variant	Exon 46 of 46	5		ENSP00000489777.1
CACNA1A	ENST00000636549.1	c.*179_*187dupCAGCAGCAG		downstream_gene_variant		5		ENSP00000490578.1
CACNA1A	ENST00000637927.1	c.*179_*187dupCAGCAGCAG		downstream_gene_variant		5		ENSP00000489715.1

Frequencies

GnomAD3 genomes AF: 0.000968 AC: 143 AN: 147800 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.000424

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000334

Gnomad ASJ AF: 0.000291

Gnomad EAS AF: 0.0141

Gnomad SAS AF: 0.000425

Gnomad FIN AF: 0.000301

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000661

Gnomad OTH AF: 0.00148

GnomAD4 exome AF: 0.00120 AC: 1546 AN: 1283864 Hom.: 9 Cov.: 0 AF XY: 0.00117 AC XY: 739 AN XY: 631906

Gnomad4 AFR exome AF: 0.000281

Gnomad4 AMR exome AF: 0.000581

Gnomad4 ASJ exome AF: 0.000138

Gnomad4 EAS exome AF: 0.0215

Gnomad4 SAS exome AF: 0.000671

Gnomad4 FIN exome AF: 0.0000898

Gnomad4 NFE exome AF: 0.000742

Gnomad4 OTH exome AF: 0.00126

GnomAD4 genome AF: 0.000960 AC: 142 AN: 147902 Hom.: 0 Cov.: 0 AF XY: 0.000986 AC XY: 71 AN XY: 72000

Gnomad4 AFR AF: 0.000423

Gnomad4 AMR AF: 0.000334

Gnomad4 ASJ AF: 0.000291

Gnomad4 EAS AF: 0.0139

Gnomad4 SAS AF: 0.000425

Gnomad4 FIN AF: 0.000301

Gnomad4 NFE AF: 0.000661

Gnomad4 OTH AF: 0.00147

Bravo AF: 0.000873

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:1

Jan 16, 2024

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Reported using an alternate transcript of the gene; Not observed at significant frequency in large population cohorts (gnomAD); In-frame duplication of 3 amino acids in a repetitive region with no known function; Has not been previously published as pathogenic or benign to our knowledge -

Feb 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

CACNA1A: BS1 -

Spinocerebellar ataxia type 6 Uncertain:1

Dec 18, 2024

Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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;