19-13286672-C-T

Position:

• chr19-13286672-C-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_001127222.2(CACNA1A):​c.3384G>A​(p.Pro1128Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000291 in 1,562,274 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 0.00027 (0 hom., cov: 30)
  • Exomes 𝑓: 0.00029 (0 hom.)
• Consequence: CACNA1A NM_001127222.2 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.674

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

Verdict is Benign. Variant got -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.28).
• BP6: Variant 19-13286672-C-T is Benign according to our data. Variant chr19-13286672-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 384063.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-13286672-C-T is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-0.674 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000265 (40/150832) while in subpopulation NFE AF= 0.000502 (34/67722). AF 95% confidence interval is 0.000369. There are 0 homozygotes in gnomad4. There are 21 alleles in male gnomad4 subpopulation. Median coverage is 30. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 40 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CACNA1A	NM_001127222.2	c.3384G>A	p.Pro1128Pro	synonymous_variant	20/47	ENST00000360228.11	NP_001120694.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CACNA1A	ENST00000360228.11	c.3384G>A	p.Pro1128Pro	synonymous_variant	20/47	1	NM_001127222.2	ENSP00000353362.5
CACNA1A	ENST00000638029.1	c.3396G>A	p.Pro1132Pro	synonymous_variant	20/48	5		ENSP00000489829.1
CACNA1A	ENST00000573710.7	c.3390G>A	p.Pro1130Pro	synonymous_variant	20/47	5		ENSP00000460092.3
CACNA1A	ENST00000635727.1	c.3387G>A	p.Pro1129Pro	synonymous_variant	20/47	5		ENSP00000490001.1
CACNA1A	ENST00000637769.1	c.3387G>A	p.Pro1129Pro	synonymous_variant	20/47	1		ENSP00000489778.1
CACNA1A	ENST00000636012.1	c.3387G>A	p.Pro1129Pro	synonymous_variant	20/46	5		ENSP00000490223.1
CACNA1A	ENST00000637736.1	c.3246G>A	p.Pro1082Pro	synonymous_variant	19/46	5		ENSP00000489861.1
CACNA1A	ENST00000636389.1	c.3387G>A	p.Pro1129Pro	synonymous_variant	20/47	5		ENSP00000489992.1
CACNA1A	ENST00000637432.1	c.3396G>A	p.Pro1132Pro	synonymous_variant	20/48	5		ENSP00000490617.1
CACNA1A	ENST00000636549.1	c.3387G>A	p.Pro1129Pro	synonymous_variant	20/48	5		ENSP00000490578.1
CACNA1A	ENST00000637927.1	c.3390G>A	p.Pro1130Pro	synonymous_variant	20/47	5		ENSP00000489715.1
CACNA1A	ENST00000635895.1	c.3387G>A	p.Pro1129Pro	synonymous_variant	20/47	5		ENSP00000490323.1
CACNA1A	ENST00000638009.2	c.3387G>A	p.Pro1129Pro	synonymous_variant	20/47	1		ENSP00000489913.1
CACNA1A	ENST00000637276.1	c.3387G>A	p.Pro1129Pro	synonymous_variant	20/46	5		ENSP00000489777.1

Frequencies

GnomAD3 genomes AF: 0.000265 AC: 40 AN: 150832 Hom.: 0 Cov.: 30

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000660

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000383

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000502

Gnomad OTH AF: 0.000488

GnomAD3 exomes AF: 0.000211 AC: 44 AN: 208124 Hom.: 0 AF XY: 0.000225 AC XY: 25 AN XY: 111164

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000909

Gnomad FIN exome AF: 0.000227

Gnomad NFE exome AF: 0.000380

Gnomad OTH exome AF: 0.000401

GnomAD4 exome AF: 0.000294 AC: 415 AN: 1411442 Hom.: 0 Cov.: 35 AF XY: 0.000283 AC XY: 197 AN XY: 695868

Gnomad4 AFR exome AF: 0.0000309

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000116

Gnomad4 FIN exome AF: 0.000401

Gnomad4 NFE exome AF: 0.000335

Gnomad4 OTH exome AF: 0.000360

GnomAD4 genome AF: 0.000265 AC: 40 AN: 150832 Hom.: 0 Cov.: 30 AF XY: 0.000286 AC XY: 21 AN XY: 73552

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.0000660

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000383

Gnomad4 NFE AF: 0.000502

Gnomad4 OTH AF: 0.000488

Alfa AF: 0.000172 Hom.: 0

Bravo AF: 0.000215

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Mar 01, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2023	CACNA1A: BP4, BP7 -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	May 22, 2020	- -

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

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 29, 2024

- -

Inborn genetic diseases Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 30, 2018

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.28
CADD	Benign	11
DANN	Benign	0.85

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

Publications

LitVar

Other links and lift over

dbSNP: rs370541345; hg19: chr19-13397486;