NM_001127222.2:c.4590+133A>G

Variant names:

• chr19-13257217-T-C
• rs4926242
• NM_001127222.2:c.4590+133A>G

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_001127222.2(CACNA1A):​c.4590+133A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.913 in 667,660 control chromosomes in the GnomAD database, including 278,449 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.92 (64931 hom., cov: 31)
  • Exomes 𝑓: 0.91 (213518 hom.)
• Consequence: CACNA1A NM_001127222.2 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -3.39
• Publications: 5 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BP6: Variant 19-13257217-T-C is Benign according to our data. Variant chr19-13257217-T-C is described in ClinVar as Benign. ClinVar VariationId is 1292944.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.96 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.4590+133A>G		intron	N/A	NP_001120694.1
	CACNA1A	NM_001127221.2	MANE Plus Clinical	c.4593+133A>G		intron	N/A	NP_001120693.1
	CACNA1A	NM_023035.3		c.4602+133A>G		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.4590+133A>G		intron	N/A	ENSP00000353362.5
	CACNA1A	ENST00000638009.2	TSL:1 MANE Plus Clinical	c.4593+133A>G		intron	N/A	ENSP00000489913.1
	CACNA1A	ENST00000638029.1	TSL:5	c.4602+133A>G		intron	N/A	ENSP00000489829.1

Frequencies

GnomAD3 genomes AF: 0.923 AC: 140365 AN: 152150 Hom.: 64869 Cov.: 31

Gnomad AFR AF: 0.967

Gnomad AMI AF: 0.678

Gnomad AMR AF: 0.945

Gnomad ASJ AF: 0.912

Gnomad EAS AF: 0.983

Gnomad SAS AF: 0.900

Gnomad FIN AF: 0.910

Gnomad MID AF: 0.946

Gnomad NFE AF: 0.893

Gnomad OTH AF: 0.927

GnomAD4 exome AF: 0.910 AC: 468791 AN: 515392 Hom.: 213518 Cov.: 7 AF XY: 0.908 AC XY: 245873 AN XY: 270798

African (AFR) AF: 0.968 AC: 13070 AN: 13496

American (AMR) AF: 0.953 AC: 18713 AN: 19644

Ashkenazi Jewish (ASJ) AF: 0.908 AC: 12722 AN: 14016

East Asian (EAS) AF: 0.990 AC: 31041 AN: 31366

South Asian (SAS) AF: 0.903 AC: 41790 AN: 46282

European-Finnish (FIN) AF: 0.913 AC: 37483 AN: 41076

Middle Eastern (MID) AF: 0.941 AC: 1932 AN: 2054

European-Non Finnish (NFE) AF: 0.896 AC: 286533 AN: 319690

Other (OTH) AF: 0.919 AC: 25507 AN: 27768

GnomAD4 genome AF: 0.923 AC: 140486 AN: 152268 Hom.: 64931 Cov.: 31 AF XY: 0.923 AC XY: 68688 AN XY: 74434

African (AFR) AF: 0.967 AC: 40210 AN: 41566

American (AMR) AF: 0.945 AC: 14451 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.912 AC: 3167 AN: 3472

East Asian (EAS) AF: 0.983 AC: 5085 AN: 5174

South Asian (SAS) AF: 0.901 AC: 4340 AN: 4818

European-Finnish (FIN) AF: 0.910 AC: 9646 AN: 10604

Middle Eastern (MID) AF: 0.949 AC: 279 AN: 294

European-Non Finnish (NFE) AF: 0.893 AC: 60728 AN: 68020

Other (OTH) AF: 0.927 AC: 1962 AN: 2116

Alfa AF: 0.908 Hom.: 73106

Bravo AF: 0.929

Asia WGS AF: 0.945 AC: 3288 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.033
DANN	Benign	0.43
PhyloP100		-3.4
PromoterAI		0.032	Neutral
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: rs4926242; hg19: chr19-13368031;