rs374613316

Variant names:

• chr19-13245236-G-A
• rs374613316
• NM_001127222.2:c.4896C>T

Variant summary

Our verdict is Benign. The variant received -15 ACMG points: 0P and 15B. BP4_Moderate BP6_Very_Strong BP7 BS2

The NM_001127222.2(CACNA1A):​c.4896C>T​(p.Phe1632Phe) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000297 in 1,613,812 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: 𝑓 0.000046 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000028 (0 hom.)
• Consequence: CACNA1A NM_001127222.2 synonymous
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.92

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]

ACMG classification

Our verdict: Benign. The variant received -15 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.31).
• BP6: Variant 19-13245236-G-A is Benign according to our data. Variant chr19-13245236-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 476262.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=1.92 with no splicing effect.
• BS2: High AC in GnomAd4 at 7 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1A	NM_001127222.2	c.4896C>T	p.Phe1632Phe	synonymous_variant	Exon 31 of 47	ENST00000360228.11	NP_001120694.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CACNA1A	ENST00000360228.11	c.4896C>T	p.Phe1632Phe	synonymous_variant	Exon 31 of 47	1	NM_001127222.2	ENSP00000353362.5
CACNA1A	ENST00000638029.1	c.4908C>T	p.Phe1636Phe	synonymous_variant	Exon 31 of 48	5		ENSP00000489829.1
CACNA1A	ENST00000573710.7	c.4902C>T	p.Phe1634Phe	synonymous_variant	Exon 31 of 47	5		ENSP00000460092.3
CACNA1A	ENST00000635727.1	c.4899C>T	p.Phe1633Phe	synonymous_variant	Exon 31 of 47	5		ENSP00000490001.1
CACNA1A	ENST00000637769.1	c.4899C>T	p.Phe1633Phe	synonymous_variant	Exon 31 of 47	1		ENSP00000489778.1
CACNA1A	ENST00000636012.1	c.4899C>T	p.Phe1633Phe	synonymous_variant	Exon 31 of 46	5		ENSP00000490223.1
CACNA1A	ENST00000637736.1	c.4758C>T	p.Phe1586Phe	synonymous_variant	Exon 30 of 46	5		ENSP00000489861.1
CACNA1A	ENST00000636389.1	c.4899C>T	p.Phe1633Phe	synonymous_variant	Exon 31 of 47	5		ENSP00000489992.1
CACNA1A	ENST00000637432.1	c.4908C>T	p.Phe1636Phe	synonymous_variant	Exon 31 of 48	5		ENSP00000490617.1
CACNA1A	ENST00000636549.1	c.4899C>T	p.Phe1633Phe	synonymous_variant	Exon 31 of 48	5		ENSP00000490578.1
CACNA1A	ENST00000637927.1	c.4902C>T	p.Phe1634Phe	synonymous_variant	Exon 31 of 47	5		ENSP00000489715.1
CACNA1A	ENST00000635895.1	c.4899C>T	p.Phe1633Phe	synonymous_variant	Exon 31 of 47	5		ENSP00000490323.1
CACNA1A	ENST00000638009.2	c.4899C>T	p.Phe1633Phe	synonymous_variant	Exon 31 of 47	1		ENSP00000489913.1
CACNA1A	ENST00000637276.1	c.4899C>T	p.Phe1633Phe	synonymous_variant	Exon 31 of 46	5		ENSP00000489777.1
CACNA1A	ENST00000636768.2	n.4899C>T		non_coding_transcript_exon_variant	Exon 31 of 45	5		ENSP00000490190.2
CACNA1A	ENST00000713789.1	n.4896C>T		non_coding_transcript_exon_variant	Exon 31 of 47			ENSP00000519091.1

Frequencies

GnomAD3 genomes AF: 0.0000460 AC: 7 AN: 152222 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000441 AC: 11 AN: 249232 AF XY: 0.0000370

Gnomad AFR exome AF: 0.000258

Gnomad AMR exome AF: 0.0000579

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000354

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000281 AC: 41 AN: 1461590 Hom.: 0 Cov.: 31 AF XY: 0.0000330 AC XY: 24 AN XY: 727086

African (AFR) AF: 0.000209 AC: 7 AN: 33480

American (AMR) AF: 0.0000447 AC: 2 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86252

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53398

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

European-Non Finnish (NFE) AF: 0.0000279 AC: 31 AN: 1111764

Other (OTH) AF: 0.00 AC: 0 AN: 60370

GnomAD4 genome AF: 0.0000460 AC: 7 AN: 152222 Hom.: 0 Cov.: 33 AF XY: 0.0000403 AC XY: 3 AN XY: 74358

African (AFR) AF: 0.000121 AC: 5 AN: 41456

American (AMR) AF: 0.00 AC: 0 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5194

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68044

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.000135 Hom.: 0

Bravo AF: 0.0000642

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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

Jan 22, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:1

Jan 30, 2021

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.31
CADD	Benign	12
DANN	Benign	0.71
PhyloP100		1.9

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.10		Details are displayed if max score is > 0.2

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

Publications

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Other links and lift over

dbSNP: rs374613316; hg19: chr19-13356050; COSMIC: COSV64212697; COSMIC: COSV64212697;