19-13267051-A-G

Variant names:

• chr19-13267051-A-G
• rs7249323
• NM_001127222.2:c.3990-4218T>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.3990-4218T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.433 in 151,854 control chromosomes in the GnomAD database, including 15,877 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 0.43 (15877 hom., cov: 31)
• Consequence: CACNA1A NM_001127222.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.283
• Publications: 6 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=-0.92).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.616 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1A	NM_001127222.2	c.3990-4218T>C		intron_variant	Intron 24 of 46	ENST00000360228.11	NP_001120694.1
CACNA1A	NM_001127221.2	c.3993-4218T>C		intron_variant	Intron 24 of 46	ENST00000638009.2	NP_001120693.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CACNA1A	ENST00000360228.11	c.3990-4218T>C		intron_variant	Intron 24 of 46	1	NM_001127222.2	ENSP00000353362.5
CACNA1A	ENST00000638009.2	c.3993-4218T>C		intron_variant	Intron 24 of 46	1	NM_001127221.2	ENSP00000489913.1
CACNA1A	ENST00000638029.1	c.4002-4218T>C		intron_variant	Intron 24 of 47	5		ENSP00000489829.1
CACNA1A	ENST00000573710.7	c.3996-4218T>C		intron_variant	Intron 24 of 46	5		ENSP00000460092.3
CACNA1A	ENST00000635727.1	c.3993-4218T>C		intron_variant	Intron 24 of 46	5		ENSP00000490001.1
CACNA1A	ENST00000637769.1	c.3993-4218T>C		intron_variant	Intron 24 of 46	1		ENSP00000489778.1
CACNA1A	ENST00000636012.1	c.3993-4218T>C		intron_variant	Intron 24 of 45	5		ENSP00000490223.1
CACNA1A	ENST00000637736.1	c.3852-4218T>C		intron_variant	Intron 23 of 45	5		ENSP00000489861.1
CACNA1A	ENST00000636389.1	c.3993-4218T>C		intron_variant	Intron 24 of 46	5		ENSP00000489992.1
CACNA1A	ENST00000637432.1	c.4002-4218T>C		intron_variant	Intron 24 of 47	5		ENSP00000490617.1
CACNA1A	ENST00000636549.1	c.3993-4218T>C		intron_variant	Intron 24 of 47	5		ENSP00000490578.1
CACNA1A	ENST00000637927.1	c.3996-4218T>C		intron_variant	Intron 24 of 46	5		ENSP00000489715.1
CACNA1A	ENST00000635895.1	c.3993-4218T>C		intron_variant	Intron 24 of 46	5		ENSP00000490323.1
CACNA1A	ENST00000637276.1	c.3993-4218T>C		intron_variant	Intron 24 of 45	5		ENSP00000489777.1
CACNA1A	ENST00000636768.2	n.3993-4218T>C		intron_variant	Intron 24 of 44	5		ENSP00000490190.2
CACNA1A	ENST00000713789.1	n.3990-4218T>C		intron_variant	Intron 24 of 46			ENSP00000519091.1

Frequencies

GnomAD3 genomes AF: 0.433 AC: 65681 AN: 151736 Hom.: 15811 Cov.: 31

Gnomad AFR AF: 0.603

Gnomad AMI AF: 0.144

Gnomad AMR AF: 0.525

Gnomad ASJ AF: 0.356

Gnomad EAS AF: 0.592

Gnomad SAS AF: 0.635

Gnomad FIN AF: 0.358

Gnomad MID AF: 0.471

Gnomad NFE AF: 0.302

Gnomad OTH AF: 0.428

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

GnomAD4 genome AF: 0.433 AC: 65810 AN: 151854 Hom.: 15877 Cov.: 31 AF XY: 0.440 AC XY: 32677 AN XY: 74188

African (AFR) AF: 0.604 AC: 24986 AN: 41382

American (AMR) AF: 0.526 AC: 8014 AN: 15242

Ashkenazi Jewish (ASJ) AF: 0.356 AC: 1235 AN: 3472

East Asian (EAS) AF: 0.592 AC: 3050 AN: 5152

South Asian (SAS) AF: 0.635 AC: 3047 AN: 4800

European-Finnish (FIN) AF: 0.358 AC: 3783 AN: 10558

Middle Eastern (MID) AF: 0.473 AC: 138 AN: 292

European-Non Finnish (NFE) AF: 0.302 AC: 20508 AN: 67934

Other (OTH) AF: 0.435 AC: 918 AN: 2110

Alfa AF: 0.348 Hom.: 11352

Bravo AF: 0.453

Asia WGS AF: 0.644 AC: 2239 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	3.1
DANN	Benign	0.58
PhyloP100		0.28
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: rs7249323; hg19: chr19-13377865;