19-13451411-A-G

Variant names:

• chr19-13451411-A-G
• rs11882861
• NM_001127222.2:c.539+1465T>C

Variant summary

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

The NM_001127222.2(CACNA1A):​c.539+1465T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.205 in 152,150 control chromosomes in the GnomAD database, including 4,454 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 0.20 (4454 hom., cov: 32)
  • Exomes 𝑓: 0.080 (0 hom.)
• Consequence: CACNA1A NM_001127222.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.687
• 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.499 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1A	NM_001127222.2	c.539+1465T>C		intron_variant	Intron 3 of 46	ENST00000360228.11	NP_001120694.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CACNA1A	ENST00000360228.11	c.539+1465T>C		intron_variant	Intron 3 of 46	1	NM_001127222.2	ENSP00000353362.5
CACNA1A	ENST00000638029.1	c.539+1465T>C		intron_variant	Intron 3 of 47	5		ENSP00000489829.1
CACNA1A	ENST00000573710.7	c.539+1465T>C		intron_variant	Intron 3 of 46	5		ENSP00000460092.3
CACNA1A	ENST00000635727.1	c.539+1465T>C		intron_variant	Intron 3 of 46	5		ENSP00000490001.1
CACNA1A	ENST00000637769.1	c.539+1465T>C		intron_variant	Intron 3 of 46	1		ENSP00000489778.1
CACNA1A	ENST00000636012.1	c.539+1465T>C		intron_variant	Intron 3 of 45	5		ENSP00000490223.1
CACNA1A	ENST00000637736.1	c.398+1465T>C		intron_variant	Intron 2 of 45	5		ENSP00000489861.1
CACNA1A	ENST00000636389.1	c.539+1465T>C		intron_variant	Intron 3 of 46	5		ENSP00000489992.1
CACNA1A	ENST00000637432.1	c.539+1465T>C		intron_variant	Intron 3 of 47	5		ENSP00000490617.1
CACNA1A	ENST00000636549.1	c.539+1465T>C		intron_variant	Intron 3 of 47	5		ENSP00000490578.1
CACNA1A	ENST00000637927.1	c.539+1465T>C		intron_variant	Intron 3 of 46	5		ENSP00000489715.1
CACNA1A	ENST00000635895.1	c.539+1465T>C		intron_variant	Intron 3 of 46	5		ENSP00000490323.1
CACNA1A	ENST00000638009.2	c.539+1465T>C		intron_variant	Intron 3 of 46	1		ENSP00000489913.1
CACNA1A	ENST00000637276.1	c.539+1465T>C		intron_variant	Intron 3 of 45	5		ENSP00000489777.1
CACNA1A	ENST00000636768.2	n.539+1465T>C		intron_variant	Intron 3 of 44	5		ENSP00000490190.2
CACNA1A	ENST00000713789.1	n.539+1465T>C		intron_variant	Intron 3 of 46			ENSP00000519091.1

Frequencies

GnomAD3 genomes AF: 0.205 AC: 31121 AN: 151982 Hom.: 4434 Cov.: 32

Gnomad AFR AF: 0.367

Gnomad AMI AF: 0.0482

Gnomad AMR AF: 0.170

Gnomad ASJ AF: 0.0928

Gnomad EAS AF: 0.516

Gnomad SAS AF: 0.211

Gnomad FIN AF: 0.149

Gnomad MID AF: 0.104

Gnomad NFE AF: 0.108

Gnomad OTH AF: 0.169

GnomAD4 exome AF: 0.0800 AC: 4 AN: 50 Hom.: 0 Cov.: 0 AF XY: 0.111 AC XY: 4 AN XY: 36

African (AFR) AC: 0 AN: 0

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AF: 0.500 AC: 1 AN: 2

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.0250 AC: 1 AN: 40

Other (OTH) AF: 0.333 AC: 2 AN: 6

GnomAD4 genome AF: 0.205 AC: 31180 AN: 152100 Hom.: 4454 Cov.: 32 AF XY: 0.208 AC XY: 15498 AN XY: 74346

African (AFR) AF: 0.367 AC: 15229 AN: 41458

American (AMR) AF: 0.171 AC: 2606 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.0928 AC: 322 AN: 3470

East Asian (EAS) AF: 0.515 AC: 2663 AN: 5166

South Asian (SAS) AF: 0.210 AC: 1013 AN: 4816

European-Finnish (FIN) AF: 0.149 AC: 1576 AN: 10592

Middle Eastern (MID) AF: 0.109 AC: 32 AN: 294

European-Non Finnish (NFE) AF: 0.108 AC: 7329 AN: 68002

Other (OTH) AF: 0.173 AC: 366 AN: 2114

Alfa AF: 0.123 Hom.: 830

Bravo AF: 0.213

Asia WGS AF: 0.354 AC: 1229 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	7.7
DANN	Benign	0.75
PhyloP100		0.69
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: rs11882861; hg19: chr19-13562225;