rs17846921

Positions:

• chr19-13224746-G-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6 BP7 BS1 BS2

The NM_001127222.2(CACNA1A):​c.5652C>T​(p.Val1884Val) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000207 in 1,610,014 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00022 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00021 (2 hom.)
• Consequence: CACNA1A NM_001127222.2 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:3
• Conservation: PhyloP100: -6.10

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.73).
• BP6: Variant 19-13224746-G-A is Benign according to our data. Variant chr19-13224746-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 284158.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1, Benign=2}.
• BP7: Synonymous conserved (PhyloP=-6.1 with no splicing effect.
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.000223 (34/152184) while in subpopulation EAS AF= 0.00348 (18/5166). AF 95% confidence interval is 0.00225. There are 0 homozygotes in gnomad4. There are 21 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 34 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CACNA1A	NM_001127222.2	c.5652C>T	p.Val1884Val	synonymous_variant	38/47	ENST00000360228.11	NP_001120694.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CACNA1A	ENST00000360228.11	c.5652C>T	p.Val1884Val	synonymous_variant	38/47	1	NM_001127222.2	ENSP00000353362.5
CACNA1A	ENST00000638029.1	c.5670C>T	p.Val1890Val	synonymous_variant	39/48	5		ENSP00000489829.1
CACNA1A	ENST00000573710.7	c.5658C>T	p.Val1886Val	synonymous_variant	38/47	5		ENSP00000460092.3
CACNA1A	ENST00000635727.1	c.5655C>T	p.Val1885Val	synonymous_variant	38/47	5		ENSP00000490001.1
CACNA1A	ENST00000637769.1	c.5655C>T	p.Val1885Val	synonymous_variant	38/47	1		ENSP00000489778.1
CACNA1A	ENST00000636012.1	c.5655C>T	p.Val1885Val	synonymous_variant	38/46	5		ENSP00000490223.1
CACNA1A	ENST00000637736.1	c.5514C>T	p.Val1838Val	synonymous_variant	37/46	5		ENSP00000489861.1
CACNA1A	ENST00000636389.1	c.5655C>T	p.Val1885Val	synonymous_variant	38/47	5		ENSP00000489992.1
CACNA1A	ENST00000637432.1	c.5670C>T	p.Val1890Val	synonymous_variant	39/48	5		ENSP00000490617.1
CACNA1A	ENST00000636549.1	c.5661C>T	p.Val1887Val	synonymous_variant	39/48	5		ENSP00000490578.1
CACNA1A	ENST00000637927.1	c.5658C>T	p.Val1886Val	synonymous_variant	38/47	5		ENSP00000489715.1
CACNA1A	ENST00000635895.1	c.5655C>T	p.Val1885Val	synonymous_variant	38/47	5		ENSP00000490323.1
CACNA1A	ENST00000638009.2	c.5655C>T	p.Val1885Val	synonymous_variant	38/47	1		ENSP00000489913.1
CACNA1A	ENST00000637276.1	c.5655C>T	p.Val1885Val	synonymous_variant	38/46	5		ENSP00000489777.1
CACNA1A	ENST00000636768.1	n.182C>T		non_coding_transcript_exon_variant	3/10	5		ENSP00000490190.2

Frequencies

GnomAD3 genomes AF: 0.000230 AC: 35 AN: 152066 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00346

Gnomad EAS AF: 0.00348

Gnomad SAS AF: 0.000415

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.000479

GnomAD3 exomes AF: 0.000480 AC: 115 AN: 239782 Hom.: 1 AF XY: 0.000390 AC XY: 51 AN XY: 130612

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00426

Gnomad EAS exome AF: 0.00344

Gnomad SAS exome AF: 0.000238

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000461

Gnomad OTH exome AF: 0.000171

GnomAD4 exome AF: 0.000205 AC: 299 AN: 1457830 Hom.: 2 Cov.: 31 AF XY: 0.000206 AC XY: 149 AN XY: 724852

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00334

Gnomad4 EAS exome AF: 0.00407

Gnomad4 SAS exome AF: 0.000117

Gnomad4 FIN exome AF: 0.0000189

Gnomad4 NFE exome AF: 0.0000180

Gnomad4 OTH exome AF: 0.000332

GnomAD4 genome AF: 0.000223 AC: 34 AN: 152184 Hom.: 0 Cov.: 31 AF XY: 0.000282 AC XY: 21 AN XY: 74400

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00346

Gnomad4 EAS AF: 0.00348

Gnomad4 SAS AF: 0.000208

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.000474

Alfa AF: 0.000398 Hom.: 0

Bravo AF: 0.000374

Asia WGS AF: 0.00231 AC: 8 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Oct 29, 2015	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 30, 2020	- -

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

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 11, 2023

- -

Inborn genetic diseases Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 17, 2017

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	-0.73
CADD	Benign	0.67
DANN	Benign	0.75

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs17846921; hg19: chr19-13335560;