19-13529121-G-C

Variant names:

• chr19-13529121-G-C
• rs12975717
• ENST00000664864.1:c.195-22896C>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The ENST00000664864.1(CACNA1A):​c.195-22896C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.158 in 152,064 control chromosomes in the GnomAD database, including 2,476 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.16 (2476 hom., cov: 32)
• Consequence: CACNA1A ENST00000664864.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.365
• Publications: 1 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.52).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.207 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CACNA1A	ENST00000664864.1	c.195-22896C>G		intron_variant	Intron 1 of 48			ENSP00000499449.1
CACNA1A	ENST00000592864.3	c.195-9618C>G		intron_variant	Intron 2 of 2	3		ENSP00000464729.2
CACNA1A	ENST00000573891.7	n.12-22896C>G		intron_variant	Intron 1 of 47	5		ENSP00000460276.2
CACNA1A	ENST00000574974.4	n.315+70632C>G		intron_variant	Intron 2 of 47	5		ENSP00000459963.3

Frequencies

GnomAD3 genomes AF: 0.159 AC: 24095 AN: 151946 Hom.: 2477 Cov.: 32

Gnomad AFR AF: 0.0387

Gnomad AMI AF: 0.0877

Gnomad AMR AF: 0.176

Gnomad ASJ AF: 0.102

Gnomad EAS AF: 0.149

Gnomad SAS AF: 0.185

Gnomad FIN AF: 0.301

Gnomad MID AF: 0.0637

Gnomad NFE AF: 0.209

Gnomad OTH AF: 0.135

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.158 AC: 24091 AN: 152064 Hom.: 2476 Cov.: 32 AF XY: 0.163 AC XY: 12084 AN XY: 74326

African (AFR) AF: 0.0386 AC: 1604 AN: 41518

American (AMR) AF: 0.176 AC: 2686 AN: 15258

Ashkenazi Jewish (ASJ) AF: 0.102 AC: 355 AN: 3468

East Asian (EAS) AF: 0.149 AC: 770 AN: 5154

South Asian (SAS) AF: 0.184 AC: 887 AN: 4816

European-Finnish (FIN) AF: 0.301 AC: 3174 AN: 10562

Middle Eastern (MID) AF: 0.0582 AC: 17 AN: 292

European-Non Finnish (NFE) AF: 0.209 AC: 14236 AN: 67972

Other (OTH) AF: 0.134 AC: 282 AN: 2112

Alfa AF: 0.0993 Hom.: 187

Bravo AF: 0.143

Asia WGS AF: 0.117 AC: 411 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.52
CADD	Benign	14
DANN	Benign	0.90
PhyloP100		0.36
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs12975717; hg19: chr19-13639935;