19-13253021-A-G

Variant names:

• chr19-13253021-A-G
• rs781413708
• NM_001127222.2:c.4836T>C

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 2P and 7B. PM2 BP4_Strong BP6_Moderate BP7

The NM_001127222.2(CACNA1A):​c.4836T>C​(p.Cys1612Cys) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,184 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: CACNA1A NM_001127222.2 synonymous
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.276
• Publications: 0 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: Likely_benign. The variant received -5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 19-13253021-A-G is Benign according to our data. Variant chr19-13253021-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 746149.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=0.276 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1A	NM_001127222.2	c.4836T>C	p.Cys1612Cys	synonymous_variant	Exon 30 of 47	ENST00000360228.11	NP_001120694.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CACNA1A	ENST00000360228.11	c.4836T>C	p.Cys1612Cys	synonymous_variant	Exon 30 of 47	1	NM_001127222.2	ENSP00000353362.5
CACNA1A	ENST00000638029.1	c.4848T>C	p.Cys1616Cys	synonymous_variant	Exon 30 of 48	5		ENSP00000489829.1
CACNA1A	ENST00000573710.7	c.4842T>C	p.Cys1614Cys	synonymous_variant	Exon 30 of 47	5		ENSP00000460092.3
CACNA1A	ENST00000635727.1	c.4839T>C	p.Cys1613Cys	synonymous_variant	Exon 30 of 47	5		ENSP00000490001.1
CACNA1A	ENST00000637769.1	c.4839T>C	p.Cys1613Cys	synonymous_variant	Exon 30 of 47	1		ENSP00000489778.1
CACNA1A	ENST00000636012.1	c.4839T>C	p.Cys1613Cys	synonymous_variant	Exon 30 of 46	5		ENSP00000490223.1
CACNA1A	ENST00000637736.1	c.4698T>C	p.Cys1566Cys	synonymous_variant	Exon 29 of 46	5		ENSP00000489861.1
CACNA1A	ENST00000636389.1	c.4839T>C	p.Cys1613Cys	synonymous_variant	Exon 30 of 47	5		ENSP00000489992.1
CACNA1A	ENST00000637432.1	c.4848T>C	p.Cys1616Cys	synonymous_variant	Exon 30 of 48	5		ENSP00000490617.1
CACNA1A	ENST00000636549.1	c.4839T>C	p.Cys1613Cys	synonymous_variant	Exon 30 of 48	5		ENSP00000490578.1
CACNA1A	ENST00000637927.1	c.4842T>C	p.Cys1614Cys	synonymous_variant	Exon 30 of 47	5		ENSP00000489715.1
CACNA1A	ENST00000635895.1	c.4839T>C	p.Cys1613Cys	synonymous_variant	Exon 30 of 47	5		ENSP00000490323.1
CACNA1A	ENST00000638009.2	c.4839T>C	p.Cys1613Cys	synonymous_variant	Exon 30 of 47	1		ENSP00000489913.1
CACNA1A	ENST00000637276.1	c.4839T>C	p.Cys1613Cys	synonymous_variant	Exon 30 of 46	5		ENSP00000489777.1
CACNA1A	ENST00000636768.2	n.4839T>C		non_coding_transcript_exon_variant	Exon 30 of 45	5		ENSP00000490190.2
CACNA1A	ENST00000713789.1	n.4836T>C		non_coding_transcript_exon_variant	Exon 30 of 47			ENSP00000519091.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000401 AC: 1 AN: 249158 AF XY: 0.00000740

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000290

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461184 Hom.: 0 Cov.: 29 AF XY: 0.00000138 AC XY: 1 AN XY: 726926

African (AFR) AF: 0.00 AC: 0 AN: 33464

American (AMR) AF: 0.0000224 AC: 1 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26128

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.00 AC: 0 AN: 86244

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53376

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111438

Other (OTH) AF: 0.00 AC: 0 AN: 60350

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Episodic ataxia type 2;C4310716:Developmental and epileptic encephalopathy, 42 Benign:1

Oct 09, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	7.5
DANN	Benign	0.57
PhyloP100		0.28
PromoterAI		0.031	Neutral

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: rs781413708; hg19: chr19-13363835;