NM_001127222.2:c.6970_6975delCAGCAG

Variant names:

• chr19-13207858-CCTGCTG-C
• rs16054
• NM_001127222.2:c.6970_6975delCAGCAG

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.6970_6975delCAGCAG​(p.Gln2324_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 0.308 in 1,259,014 control chromosomes in the GnomAD database, including 36,422 homozygotes. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.39 (12013 hom., cov: 0)
  • Exomes 𝑓: 0.31 (36422 hom.)
  • Failed GnomAD Quality Control
• Consequence: CACNA1A NM_001127222.2 conservative_inframe_deletion
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: 0.00
• 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-CCTGCTG-C is Benign according to our data. Variant chr19-13207858-CCTGCTG-C is described in ClinVar as [Likely_benign]. Clinvar id is 445458.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAdExome4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.476 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1A	NM_001127222.2	c.6970_6975delCAGCAG	p.Gln2324_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.6970_6975delCAGCAG	p.Gln2324_Gln2325del	conservative_inframe_deletion	Exon 47 of 47	1	NM_001127222.2	ENSP00000353362.5
CACNA1A	ENST00000638029.1	c.6988_6993delCAGCAG	p.Gln2330_Gln2331del	conservative_inframe_deletion	Exon 48 of 48	5		ENSP00000489829.1
CACNA1A	ENST00000573710.7	c.6976_6981delCAGCAG	p.Gln2326_Gln2327del	conservative_inframe_deletion	Exon 47 of 47	5		ENSP00000460092.3
CACNA1A	ENST00000635727.1	c.6973_6978delCAGCAG	p.Gln2325_Gln2326del	conservative_inframe_deletion	Exon 47 of 47	5		ENSP00000490001.1
CACNA1A	ENST00000637769.1	c.6973_6978delCAGCAG	p.Gln2325_Gln2326del	conservative_inframe_deletion	Exon 47 of 47	1		ENSP00000489778.1
CACNA1A	ENST00000636012.1	c.6937_6942delCAGCAG	p.Gln2313_Gln2314del	conservative_inframe_deletion	Exon 46 of 46	5		ENSP00000490223.1
CACNA1A	ENST00000637736.1	c.6832_6837delCAGCAG	p.Gln2278_Gln2279del	conservative_inframe_deletion	Exon 46 of 46	5		ENSP00000489861.1
CACNA1A	ENST00000636768.2	n.*1231_*1236delCAGCAG		non_coding_transcript_exon_variant	Exon 45 of 45	5		ENSP00000490190.2
CACNA1A	ENST00000713789.1	n.*2149_*2154delCAGCAG		non_coding_transcript_exon_variant	Exon 47 of 47			ENSP00000519091.1
CACNA1A	ENST00000636389.1	c.*56_*61delCAGCAG		3_prime_UTR_variant	Exon 47 of 47	5		ENSP00000489992.1
CACNA1A	ENST00000637432.1	c.*182_*187delCAGCAG		3_prime_UTR_variant	Exon 48 of 48	5		ENSP00000490617.1
CACNA1A	ENST00000635895.1	c.*182_*187delCAGCAG		3_prime_UTR_variant	Exon 47 of 47	5		ENSP00000490323.1
CACNA1A	ENST00000638009.2	c.*182_*187delCAGCAG		3_prime_UTR_variant	Exon 47 of 47	1		ENSP00000489913.1
CACNA1A	ENST00000637276.1	c.*182_*187delCAGCAG		3_prime_UTR_variant	Exon 46 of 46	5		ENSP00000489777.1
CACNA1A	ENST00000636768.2	n.*1231_*1236delCAGCAG		3_prime_UTR_variant	Exon 45 of 45	5		ENSP00000490190.2
CACNA1A	ENST00000713789.1	n.*2149_*2154delCAGCAG		3_prime_UTR_variant	Exon 47 of 47			ENSP00000519091.1
CACNA1A	ENST00000636549.1	c.*182_*187delCAGCAG		downstream_gene_variant		5		ENSP00000490578.1
CACNA1A	ENST00000637927.1	c.*182_*187delCAGCAG		downstream_gene_variant		5		ENSP00000489715.1

Frequencies

GnomAD3 genomes AF: 0.389 AC: 57375 AN: 147566 Hom.: 12009 Cov.: 0

Gnomad AFR AF: 0.534

Gnomad AMI AF: 0.322

Gnomad AMR AF: 0.426

Gnomad ASJ AF: 0.431

Gnomad EAS AF: 0.202

Gnomad SAS AF: 0.403

Gnomad FIN AF: 0.228

Gnomad MID AF: 0.567

Gnomad NFE AF: 0.327

Gnomad OTH AF: 0.410

GnomAD2 exomes AF: 0.245 AC: 12734 AN: 52038 AF XY: 0.251

Gnomad AFR exome AF: 0.407

Gnomad AMR exome AF: 0.279

Gnomad ASJ exome AF: 0.283

Gnomad EAS exome AF: 0.0873

Gnomad FIN exome AF: 0.174

Gnomad NFE exome AF: 0.224

Gnomad OTH exome AF: 0.258

GnomAD4 exome AF: 0.308 AC: 387948 AN: 1259014 Hom.: 36422 AF XY: 0.309 AC XY: 191427 AN XY: 619668

African (AFR) AF: 0.483 AC: 11583 AN: 23976

American (AMR) AF: 0.343 AC: 8136 AN: 23694

Ashkenazi Jewish (ASJ) AF: 0.358 AC: 7622 AN: 21312

East Asian (EAS) AF: 0.209 AC: 6141 AN: 29360

South Asian (SAS) AF: 0.349 AC: 22561 AN: 64646

European-Finnish (FIN) AF: 0.225 AC: 7216 AN: 32018

Middle Eastern (MID) AF: 0.401 AC: 1485 AN: 3706

European-Non Finnish (NFE) AF: 0.304 AC: 306368 AN: 1008138

Other (OTH) AF: 0.323 AC: 16836 AN: 52164

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.389 AC: 57414 AN: 147668 Hom.: 12013 Cov.: 0 AF XY: 0.383 AC XY: 27560 AN XY: 71882

African (AFR) AF: 0.533 AC: 21381 AN: 40108

American (AMR) AF: 0.427 AC: 6381 AN: 14948

Ashkenazi Jewish (ASJ) AF: 0.431 AC: 1480 AN: 3430

East Asian (EAS) AF: 0.203 AC: 975 AN: 4810

South Asian (SAS) AF: 0.402 AC: 1890 AN: 4698

European-Finnish (FIN) AF: 0.228 AC: 2263 AN: 9924

Middle Eastern (MID) AF: 0.565 AC: 156 AN: 276

European-Non Finnish (NFE) AF: 0.327 AC: 21766 AN: 66536

Other (OTH) AF: 0.408 AC: 834 AN: 2044

Alfa AF: 0.134 Hom.: 195

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

-

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jul 15, 2024

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is classified as Benign based on local population frequency. This variant was detected in 40% of patients studied in a panel designed for Epileptic and Developmental Encephalopathy and Progressive Myoclonus Epilepsy. Number of patients: 37. Only high quality variants are reported. -

Feb 16, 2025

Laboratory of Genetics, Children's Clinical University Hospital Latvia

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:4

Jun 20, 2017

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 10, 2020

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Spinocerebellar ataxia type 6 Benign:1

Jul 14, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Episodic ataxia type 2 Benign:1

Jul 14, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Migraine, familial hemiplegic, 1 Benign:1

Jul 14, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Developmental and epileptic encephalopathy, 42 Benign:1

Jul 14, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.0
Mutation Taster		=192/8	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: COSV64196880; COSMIC: COSV64196880;