rs2074880

Variant names:

• chr19-13261817-A-C
• rs2074880
• NM_001127222.2:c.4090-207T>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.4090-207T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.327 in 553,396 control chromosomes in the GnomAD database, including 31,063 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.29 (7218 hom., cov: 32)
  • Exomes 𝑓: 0.34 (23845 hom.)
• Consequence: CACNA1A NM_001127222.2 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.369
• 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=-0.89).
• BP6: Variant 19-13261817-A-C is Benign according to our data. Variant chr19-13261817-A-C is described in ClinVar as Benign. ClinVar VariationId is 678176.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.373 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1A	NM_001127222.2	c.4090-207T>G		intron_variant	Intron 25 of 46	ENST00000360228.11	NP_001120694.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CACNA1A	ENST00000360228.11	c.4090-207T>G		intron_variant	Intron 25 of 46	1	NM_001127222.2	ENSP00000353362.5
CACNA1A	ENST00000638029.1	c.4102-207T>G		intron_variant	Intron 25 of 47	5		ENSP00000489829.1
CACNA1A	ENST00000573710.7	c.4096-207T>G		intron_variant	Intron 25 of 46	5		ENSP00000460092.3
CACNA1A	ENST00000635727.1	c.4093-207T>G		intron_variant	Intron 25 of 46	5		ENSP00000490001.1
CACNA1A	ENST00000637769.1	c.4093-207T>G		intron_variant	Intron 25 of 46	1		ENSP00000489778.1
CACNA1A	ENST00000636012.1	c.4093-207T>G		intron_variant	Intron 25 of 45	5		ENSP00000490223.1
CACNA1A	ENST00000637736.1	c.3952-207T>G		intron_variant	Intron 24 of 45	5		ENSP00000489861.1
CACNA1A	ENST00000636389.1	c.4093-207T>G		intron_variant	Intron 25 of 46	5		ENSP00000489992.1
CACNA1A	ENST00000637432.1	c.4102-207T>G		intron_variant	Intron 25 of 47	5		ENSP00000490617.1
CACNA1A	ENST00000636549.1	c.4093-207T>G		intron_variant	Intron 25 of 47	5		ENSP00000490578.1
CACNA1A	ENST00000637927.1	c.4096-207T>G		intron_variant	Intron 25 of 46	5		ENSP00000489715.1
CACNA1A	ENST00000635895.1	c.4093-207T>G		intron_variant	Intron 25 of 46	5		ENSP00000490323.1
CACNA1A	ENST00000638009.2	c.4093-207T>G		intron_variant	Intron 25 of 46	1		ENSP00000489913.1
CACNA1A	ENST00000637276.1	c.4093-207T>G		intron_variant	Intron 25 of 45	5		ENSP00000489777.1
CACNA1A	ENST00000636768.2	n.4093-207T>G		intron_variant	Intron 25 of 44	5		ENSP00000490190.2
CACNA1A	ENST00000713789.1	n.4090-207T>G		intron_variant	Intron 25 of 46			ENSP00000519091.1

Frequencies

GnomAD3 genomes AF: 0.295 AC: 44821 AN: 152030 Hom.: 7224 Cov.: 32

Gnomad AFR AF: 0.175

Gnomad AMI AF: 0.313

Gnomad AMR AF: 0.273

Gnomad ASJ AF: 0.355

Gnomad EAS AF: 0.387

Gnomad SAS AF: 0.278

Gnomad FIN AF: 0.274

Gnomad MID AF: 0.290

Gnomad NFE AF: 0.366

Gnomad OTH AF: 0.312

GnomAD4 exome AF: 0.339 AC: 135992 AN: 401248 Hom.: 23845 Cov.: 4 AF XY: 0.338 AC XY: 70898 AN XY: 210032

African (AFR) AF: 0.174 AC: 2031 AN: 11652

American (AMR) AF: 0.232 AC: 3915 AN: 16864

Ashkenazi Jewish (ASJ) AF: 0.356 AC: 4426 AN: 12442

East Asian (EAS) AF: 0.339 AC: 9759 AN: 28788

South Asian (SAS) AF: 0.291 AC: 10958 AN: 37612

European-Finnish (FIN) AF: 0.293 AC: 7808 AN: 26652

Middle Eastern (MID) AF: 0.322 AC: 565 AN: 1752

European-Non Finnish (NFE) AF: 0.366 AC: 88481 AN: 242040

Other (OTH) AF: 0.343 AC: 8049 AN: 23446

GnomAD4 genome AF: 0.294 AC: 44800 AN: 152148 Hom.: 7218 Cov.: 32 AF XY: 0.291 AC XY: 21631 AN XY: 74372

African (AFR) AF: 0.175 AC: 7250 AN: 41528

American (AMR) AF: 0.273 AC: 4168 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.355 AC: 1231 AN: 3470

East Asian (EAS) AF: 0.387 AC: 2002 AN: 5178

South Asian (SAS) AF: 0.278 AC: 1342 AN: 4826

European-Finnish (FIN) AF: 0.274 AC: 2896 AN: 10580

Middle Eastern (MID) AF: 0.284 AC: 83 AN: 292

European-Non Finnish (NFE) AF: 0.366 AC: 24893 AN: 67974

Other (OTH) AF: 0.307 AC: 650 AN: 2114

Alfa AF: 0.306 Hom.: 4181

Bravo AF: 0.289

Asia WGS AF: 0.296 AC: 1030 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Jun 14, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	1.0
DANN	Benign	0.51
PhyloP100		-0.37
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: rs2074880; hg19: chr19-13372631;