19-13298807-G-A

Position:

• chr19-13298807-G-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_001127222.2(CACNA1A):​c.2826C>T​(p.Ser942Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00106 in 1,561,392 control chromosomes in the GnomAD database, including 16 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0060 (8 hom., cov: 33)
  • Exomes 𝑓: 0.00052 (8 hom.)
• Consequence: CACNA1A NM_001127222.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.641

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.63).
• BP6: Variant 19-13298807-G-A is Benign according to our data. Variant chr19-13298807-G-A is described in ClinVar as [Benign]. Clinvar id is 385274.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-13298807-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=0.641 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00602 (917/152282) while in subpopulation AFR AF= 0.0207 (860/41566). AF 95% confidence interval is 0.0195. There are 8 homozygotes in gnomad4. There are 445 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 917 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CACNA1A	NM_001127222.2	c.2826C>T	p.Ser942Ser	synonymous_variant	19/47	ENST00000360228.11	NP_001120694.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CACNA1A	ENST00000360228.11	c.2826C>T	p.Ser942Ser	synonymous_variant	19/47	1	NM_001127222.2	ENSP00000353362.5
CACNA1A	ENST00000638029.1	c.2838C>T	p.Ser946Ser	synonymous_variant	19/48	5		ENSP00000489829.1
CACNA1A	ENST00000573710.7	c.2832C>T	p.Ser944Ser	synonymous_variant	19/47	5		ENSP00000460092.3
CACNA1A	ENST00000635727.1	c.2829C>T	p.Ser943Ser	synonymous_variant	19/47	5		ENSP00000490001.1
CACNA1A	ENST00000637769.1	c.2829C>T	p.Ser943Ser	synonymous_variant	19/47	1		ENSP00000489778.1
CACNA1A	ENST00000636012.1	c.2829C>T	p.Ser943Ser	synonymous_variant	19/46	5		ENSP00000490223.1
CACNA1A	ENST00000637736.1	c.2688C>T	p.Ser896Ser	synonymous_variant	18/46	5		ENSP00000489861.1
CACNA1A	ENST00000636389.1	c.2829C>T	p.Ser943Ser	synonymous_variant	19/47	5		ENSP00000489992.1
CACNA1A	ENST00000637432.1	c.2838C>T	p.Ser946Ser	synonymous_variant	19/48	5		ENSP00000490617.1
CACNA1A	ENST00000636549.1	c.2829C>T	p.Ser943Ser	synonymous_variant	19/48	5		ENSP00000490578.1
CACNA1A	ENST00000637927.1	c.2832C>T	p.Ser944Ser	synonymous_variant	19/47	5		ENSP00000489715.1
CACNA1A	ENST00000635895.1	c.2829C>T	p.Ser943Ser	synonymous_variant	19/47	5		ENSP00000490323.1
CACNA1A	ENST00000638009.2	c.2829C>T	p.Ser943Ser	synonymous_variant	19/47	1		ENSP00000489913.1
CACNA1A	ENST00000637276.1	c.2829C>T	p.Ser943Ser	synonymous_variant	19/46	5		ENSP00000489777.1

Frequencies

GnomAD3 genomes AF: 0.00599 AC: 912 AN: 152174 Hom.: 7 Cov.: 33

Gnomad AFR AF: 0.0206

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00295

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: 0.0000588

Gnomad OTH AF: 0.00383

GnomAD3 exomes AF: 0.00117 AC: 207 AN: 176464 Hom.: 1 AF XY: 0.000899 AC XY: 89 AN XY: 99044

Gnomad AFR exome AF: 0.0236

Gnomad AMR exome AF: 0.000917

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000440

GnomAD4 exome AF: 0.000521 AC: 734 AN: 1409110 Hom.: 8 Cov.: 32 AF XY: 0.000428 AC XY: 299 AN XY: 699234

Gnomad4 AFR exome AF: 0.0199

Gnomad4 AMR exome AF: 0.00116

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000247

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000119

Gnomad4 OTH exome AF: 0.00120

GnomAD4 genome AF: 0.00602 AC: 917 AN: 152282 Hom.: 8 Cov.: 33 AF XY: 0.00598 AC XY: 445 AN XY: 74454

Gnomad4 AFR AF: 0.0207

Gnomad4 AMR AF: 0.00294

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000588

Gnomad4 OTH AF: 0.00379

Alfa AF: 0.00322 Hom.: 1

Bravo AF: 0.00640

Asia WGS AF: 0.000872 AC: 3 AN: 3456

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Apr 21, 2016

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

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

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

Inborn genetic diseases Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 28, 2016

This alteration is classified as 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. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Athena Diagnostics

May 20, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.63
CADD	Benign	8.4
DANN	Benign	0.84

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: rs181024112; hg19: chr19-13409621; COSMIC: COSV64190552;