chr19-13207858-CCTGCTGCTGCTGCTGCTG-C

Variant names:

• chr19-13207858-CCTGCTGCTGCTGCTGCTG-C
• rs16054
• NM_001127222.2:c.6958_6975delCAGCAGCAGCAGCAGCAG

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_001127222.2(CACNA1A):​c.6958_6975delCAGCAGCAGCAGCAGCAG​(p.Gln2320_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 0.0852 in 1,278,312 control chromosomes in the GnomAD database, including 4,615 homozygotes. It is difficult to determine the true allele frequency of this variant because it is of type DEL_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. Q2320Q) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.090 (758 hom., cov: 0)
  • Exomes 𝑓: 0.085 (4615 hom.)
  • Failed GnomAD Quality Control
• Consequence: CACNA1A NM_001127222.2 conservative_inframe_deletion
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.785
• Publications: 10 publications found

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]

CACNA1A Gene-Disease associations (from GenCC):

• episodic ataxia type 2

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Ambry Genetics, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
• undetermined early-onset epileptic encephalopathy

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, Illumina
• developmental and epileptic encephalopathy, 42

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• migraine, familial hemiplegic, 1

  Inheritance: AD Classification: STRONG Submitted by: Ambry Genetics, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
• spinocerebellar ataxia type 6

  Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Ambry Genetics, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Orphanet
• benign paroxysmal torticollis of infancy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• familial or sporadic hemiplegic migraine

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Lennox-Gastaut syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000300728 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -16 ACMG points.

• BP6: Variant 19-13207858-CCTGCTGCTGCTGCTGCTG-C is Benign according to our data. Variant chr19-13207858-CCTGCTGCTGCTGCTGCTG-C is described in ClinVar as [Benign]. Clinvar id is 1249720.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAdExome4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.107 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1A	NM_001127222.2	c.6958_6975delCAGCAGCAGCAGCAGCAG	p.Gln2320_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.6958_6975delCAGCAGCAGCAGCAGCAG	p.Gln2320_Gln2325del	conservative_inframe_deletion	Exon 47 of 47	1	NM_001127222.2	ENSP00000353362.5
CACNA1A	ENST00000638029.1	c.6976_6993delCAGCAGCAGCAGCAGCAG	p.Gln2326_Gln2331del	conservative_inframe_deletion	Exon 48 of 48	5		ENSP00000489829.1
CACNA1A	ENST00000573710.7	c.6964_6981delCAGCAGCAGCAGCAGCAG	p.Gln2322_Gln2327del	conservative_inframe_deletion	Exon 47 of 47	5		ENSP00000460092.3
CACNA1A	ENST00000635727.1	c.6961_6978delCAGCAGCAGCAGCAGCAG	p.Gln2321_Gln2326del	conservative_inframe_deletion	Exon 47 of 47	5		ENSP00000490001.1
CACNA1A	ENST00000637769.1	c.6961_6978delCAGCAGCAGCAGCAGCAG	p.Gln2321_Gln2326del	conservative_inframe_deletion	Exon 47 of 47	1		ENSP00000489778.1
CACNA1A	ENST00000636012.1	c.6925_6942delCAGCAGCAGCAGCAGCAG	p.Gln2309_Gln2314del	conservative_inframe_deletion	Exon 46 of 46	5		ENSP00000490223.1
CACNA1A	ENST00000637736.1	c.6820_6837delCAGCAGCAGCAGCAGCAG	p.Gln2274_Gln2279del	conservative_inframe_deletion	Exon 46 of 46	5		ENSP00000489861.1
CACNA1A	ENST00000636768.2	n.*1219_*1236delCAGCAGCAGCAGCAGCAG		non_coding_transcript_exon_variant	Exon 45 of 45	5		ENSP00000490190.2
CACNA1A	ENST00000713789.1	n.*2137_*2154delCAGCAGCAGCAGCAGCAG		non_coding_transcript_exon_variant	Exon 47 of 47			ENSP00000519091.1
CACNA1A	ENST00000636389.1	c.*44_*61delCAGCAGCAGCAGCAGCAG		3_prime_UTR_variant	Exon 47 of 47	5		ENSP00000489992.1
CACNA1A	ENST00000637432.1	c.*170_*187delCAGCAGCAGCAGCAGCAG		3_prime_UTR_variant	Exon 48 of 48	5		ENSP00000490617.1
CACNA1A	ENST00000635895.1	c.*170_*187delCAGCAGCAGCAGCAGCAG		3_prime_UTR_variant	Exon 47 of 47	5		ENSP00000490323.1
CACNA1A	ENST00000638009.2	c.*170_*187delCAGCAGCAGCAGCAGCAG		3_prime_UTR_variant	Exon 47 of 47	1		ENSP00000489913.1
CACNA1A	ENST00000637276.1	c.*170_*187delCAGCAGCAGCAGCAGCAG		3_prime_UTR_variant	Exon 46 of 46	5		ENSP00000489777.1
CACNA1A	ENST00000636768.2	n.*1219_*1236delCAGCAGCAGCAGCAGCAG		3_prime_UTR_variant	Exon 45 of 45	5		ENSP00000490190.2
CACNA1A	ENST00000713789.1	n.*2137_*2154delCAGCAGCAGCAGCAGCAG		3_prime_UTR_variant	Exon 47 of 47			ENSP00000519091.1
CACNA1A	ENST00000636549.1	c.*170_*187delCAGCAGCAGCAGCAGCAG		downstream_gene_variant		5		ENSP00000490578.1
CACNA1A	ENST00000637927.1	c.*170_*187delCAGCAGCAGCAGCAGCAG		downstream_gene_variant		5		ENSP00000489715.1

Frequencies

GnomAD3 genomes AF: 0.0896 AC: 13235 AN: 147746 Hom.: 756 Cov.: 0

Gnomad AFR AF: 0.0579

Gnomad AMI AF: 0.0268

Gnomad AMR AF: 0.0597

Gnomad ASJ AF: 0.0562

Gnomad EAS AF: 0.0905

Gnomad SAS AF: 0.162

Gnomad FIN AF: 0.197

Gnomad MID AF: 0.0667

Gnomad NFE AF: 0.0967

Gnomad OTH AF: 0.0936

GnomAD2 exomes AF: 0.0194 AC: 1007 AN: 52038 AF XY: 0.0199

Gnomad AFR exome AF: 0.0146

Gnomad AMR exome AF: 0.00605

Gnomad ASJ exome AF: 0.00930

Gnomad EAS exome AF: 0.00420

Gnomad FIN exome AF: 0.0397

Gnomad NFE exome AF: 0.0237

Gnomad OTH exome AF: 0.0177

GnomAD4 exome AF: 0.0852 AC: 108948 AN: 1278312 Hom.: 4615 AF XY: 0.0847 AC XY: 53227 AN XY: 628184

African (AFR) AF: 0.0532 AC: 1326 AN: 24910

American (AMR) AF: 0.0274 AC: 659 AN: 24028

Ashkenazi Jewish (ASJ) AF: 0.0471 AC: 1020 AN: 21650

East Asian (EAS) AF: 0.0635 AC: 1877 AN: 29540

South Asian (SAS) AF: 0.109 AC: 7009 AN: 64032

European-Finnish (FIN) AF: 0.149 AC: 4942 AN: 33078

Middle Eastern (MID) AF: 0.0865 AC: 323 AN: 3736

European-Non Finnish (NFE) AF: 0.0853 AC: 87387 AN: 1024442

Other (OTH) AF: 0.0833 AC: 4405 AN: 52896

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.0896 AC: 13254 AN: 147848 Hom.: 758 Cov.: 0 AF XY: 0.0951 AC XY: 6847 AN XY: 71964

African (AFR) AF: 0.0579 AC: 2329 AN: 40194

American (AMR) AF: 0.0594 AC: 889 AN: 14960

Ashkenazi Jewish (ASJ) AF: 0.0562 AC: 193 AN: 3436

East Asian (EAS) AF: 0.0904 AC: 435 AN: 4812

South Asian (SAS) AF: 0.162 AC: 762 AN: 4700

European-Finnish (FIN) AF: 0.197 AC: 1957 AN: 9936

Middle Eastern (MID) AF: 0.0688 AC: 19 AN: 276

European-Non Finnish (NFE) AF: 0.0967 AC: 6441 AN: 66596

Other (OTH) AF: 0.100 AC: 205 AN: 2042

Alfa AF: 0.0669 Hom.: 195

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1

Jun 02, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 27535533) -

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

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.79
Mutation Taster		=197/3	polymorphism (auto)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs16054; hg19: chr19-13318672; COSMIC: COSV105278621; COSMIC: COSV105278621;