rs3764615

Variant names:

• chr19-13453138-C-A
• rs3764615
• NM_001127222.2:c.400-123G>T

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.400-123G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.102 in 909,456 control chromosomes in the GnomAD database, including 6,238 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.13 (1539 hom., cov: 32)
  • Exomes 𝑓: 0.097 (4699 hom.)
• Consequence: CACNA1A NM_001127222.2 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.115
• 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=-0.79).
• BP6: Variant 19-13453138-C-A is Benign according to our data. Variant chr19-13453138-C-A is described in ClinVar as Benign. ClinVar VariationId is 680137.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.249 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1A	NM_001127222.2	c.400-123G>T		intron_variant	Intron 2 of 46	ENST00000360228.11	NP_001120694.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CACNA1A	ENST00000360228.11	c.400-123G>T		intron_variant	Intron 2 of 46	1	NM_001127222.2	ENSP00000353362.5
CACNA1A	ENST00000638029.1	c.400-123G>T		intron_variant	Intron 2 of 47	5		ENSP00000489829.1
CACNA1A	ENST00000573710.7	c.400-123G>T		intron_variant	Intron 2 of 46	5		ENSP00000460092.3
CACNA1A	ENST00000635727.1	c.400-123G>T		intron_variant	Intron 2 of 46	5		ENSP00000490001.1
CACNA1A	ENST00000637769.1	c.400-123G>T		intron_variant	Intron 2 of 46	1		ENSP00000489778.1
CACNA1A	ENST00000636012.1	c.400-123G>T		intron_variant	Intron 2 of 45	5		ENSP00000490223.1
CACNA1A	ENST00000637736.1	c.259-123G>T		intron_variant	Intron 1 of 45	5		ENSP00000489861.1
CACNA1A	ENST00000636389.1	c.400-123G>T		intron_variant	Intron 2 of 46	5		ENSP00000489992.1
CACNA1A	ENST00000637432.1	c.400-123G>T		intron_variant	Intron 2 of 47	5		ENSP00000490617.1
CACNA1A	ENST00000636549.1	c.400-123G>T		intron_variant	Intron 2 of 47	5		ENSP00000490578.1
CACNA1A	ENST00000637927.1	c.400-123G>T		intron_variant	Intron 2 of 46	5		ENSP00000489715.1
CACNA1A	ENST00000635895.1	c.400-123G>T		intron_variant	Intron 2 of 46	5		ENSP00000490323.1
CACNA1A	ENST00000638009.2	c.400-123G>T		intron_variant	Intron 2 of 46	1		ENSP00000489913.1
CACNA1A	ENST00000637276.1	c.400-123G>T		intron_variant	Intron 2 of 45	5		ENSP00000489777.1
CACNA1A	ENST00000636768.2	n.400-123G>T		intron_variant	Intron 2 of 44	5		ENSP00000490190.2
CACNA1A	ENST00000713789.1	n.400-123G>T		intron_variant	Intron 2 of 46			ENSP00000519091.1

Frequencies

GnomAD3 genomes AF: 0.126 AC: 19175 AN: 151986 Hom.: 1535 Cov.: 32

Gnomad AFR AF: 0.207

Gnomad AMI AF: 0.0121

Gnomad AMR AF: 0.117

Gnomad ASJ AF: 0.0528

Gnomad EAS AF: 0.261

Gnomad SAS AF: 0.187

Gnomad FIN AF: 0.117

Gnomad MID AF: 0.0791

Gnomad NFE AF: 0.0722

Gnomad OTH AF: 0.101

GnomAD4 exome AF: 0.0967 AC: 73233 AN: 757352 Hom.: 4699 AF XY: 0.0985 AC XY: 38456 AN XY: 390552

African (AFR) AF: 0.208 AC: 3987 AN: 19212

American (AMR) AF: 0.124 AC: 3560 AN: 28754

Ashkenazi Jewish (ASJ) AF: 0.0581 AC: 984 AN: 16934

East Asian (EAS) AF: 0.251 AC: 8752 AN: 34832

South Asian (SAS) AF: 0.179 AC: 10118 AN: 56412

European-Finnish (FIN) AF: 0.107 AC: 4805 AN: 44990

Middle Eastern (MID) AF: 0.0610 AC: 228 AN: 3738

European-Non Finnish (NFE) AF: 0.0719 AC: 37134 AN: 516188

Other (OTH) AF: 0.101 AC: 3665 AN: 36292

GnomAD4 genome AF: 0.126 AC: 19205 AN: 152104 Hom.: 1539 Cov.: 32 AF XY: 0.130 AC XY: 9670 AN XY: 74366

African (AFR) AF: 0.207 AC: 8581 AN: 41468

American (AMR) AF: 0.118 AC: 1801 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.0528 AC: 183 AN: 3468

East Asian (EAS) AF: 0.261 AC: 1345 AN: 5156

South Asian (SAS) AF: 0.186 AC: 898 AN: 4818

European-Finnish (FIN) AF: 0.117 AC: 1237 AN: 10596

Middle Eastern (MID) AF: 0.0816 AC: 24 AN: 294

European-Non Finnish (NFE) AF: 0.0722 AC: 4911 AN: 68006

Other (OTH) AF: 0.101 AC: 214 AN: 2112

Alfa AF: 0.0889 Hom.: 2488

Bravo AF: 0.127

Asia WGS AF: 0.211 AC: 732 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jun 19, 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	-0.79
CADD	Benign	3.8
DANN	Benign	0.77
PhyloP100		-0.12
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: rs3764615; hg19: chr19-13563952; COSMIC: COSV64192882;