NM_001127222.2:c.3554-90G>A

Variant names:

• chr19-13285296-C-T
• rs3764580
• NM_001127222.2:c.3554-90G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001127222.2(CACNA1A):​c.3554-90G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.14 in 1,463,610 control chromosomes in the GnomAD database, including 16,924 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.12 (1656 hom., cov: 31)
  • Exomes 𝑓: 0.14 (15268 hom.)
• Consequence: CACNA1A NM_001127222.2 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.0120
• Publications: 2 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

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 19-13285296-C-T is Benign according to our data. Variant chr19-13285296-C-T is described in ClinVar as Benign. ClinVar VariationId is 1293083.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.359 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001127222.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CACNA1A	NM_001127222.2	MANE Select	c.3554-90G>A		intron	N/A	NP_001120694.1
	CACNA1A	NM_001127221.2	MANE Plus Clinical	c.3557-90G>A		intron	N/A	NP_001120693.1
	CACNA1A	NM_023035.3		c.3566-90G>A		intron	N/A	NP_075461.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CACNA1A	ENST00000360228.11	TSL:1 MANE Select	c.3554-90G>A		intron	N/A	ENSP00000353362.5
	CACNA1A	ENST00000638009.2	TSL:1 MANE Plus Clinical	c.3557-90G>A		intron	N/A	ENSP00000489913.1
	CACNA1A	ENST00000638029.1	TSL:5	c.3566-90G>A		intron	N/A	ENSP00000489829.1

Frequencies

GnomAD3 genomes AF: 0.122 AC: 18594 AN: 152024 Hom.: 1655 Cov.: 31

Gnomad AFR AF: 0.0282

Gnomad AMI AF: 0.136

Gnomad AMR AF: 0.216

Gnomad ASJ AF: 0.171

Gnomad EAS AF: 0.373

Gnomad SAS AF: 0.220

Gnomad FIN AF: 0.117

Gnomad MID AF: 0.193

Gnomad NFE AF: 0.130

Gnomad OTH AF: 0.141

GnomAD4 exome AF: 0.142 AC: 185599 AN: 1311468 Hom.: 15268 AF XY: 0.144 AC XY: 93563 AN XY: 651974

African (AFR) AF: 0.0248 AC: 739 AN: 29754

American (AMR) AF: 0.276 AC: 9546 AN: 34550

Ashkenazi Jewish (ASJ) AF: 0.173 AC: 3876 AN: 22466

East Asian (EAS) AF: 0.348 AC: 13325 AN: 38264

South Asian (SAS) AF: 0.201 AC: 15162 AN: 75446

European-Finnish (FIN) AF: 0.114 AC: 5743 AN: 50218

Middle Eastern (MID) AF: 0.208 AC: 977 AN: 4696

European-Non Finnish (NFE) AF: 0.128 AC: 128228 AN: 1001232

Other (OTH) AF: 0.146 AC: 8003 AN: 54842

GnomAD4 genome AF: 0.122 AC: 18591 AN: 152142 Hom.: 1656 Cov.: 31 AF XY: 0.127 AC XY: 9456 AN XY: 74386

African (AFR) AF: 0.0281 AC: 1166 AN: 41516

American (AMR) AF: 0.217 AC: 3314 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.171 AC: 592 AN: 3472

East Asian (EAS) AF: 0.372 AC: 1924 AN: 5166

South Asian (SAS) AF: 0.219 AC: 1056 AN: 4812

European-Finnish (FIN) AF: 0.117 AC: 1241 AN: 10592

Middle Eastern (MID) AF: 0.190 AC: 56 AN: 294

European-Non Finnish (NFE) AF: 0.130 AC: 8822 AN: 67982

Other (OTH) AF: 0.140 AC: 296 AN: 2116

Alfa AF: 0.139 Hom.: 532

Bravo AF: 0.127

Asia WGS AF: 0.259 AC: 900 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	1.5
DANN	Benign	0.36
PhyloP100		0.012
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs3764580; hg19: chr19-13396110; COSMIC: COSV64206127; COSMIC: COSV64206127;