rs374749004

Variant names:

• chr19-13286747-G-A
• rs374749004
• NM_001127222.2:c.3309C>T

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.3309C>T​(p.Pro1103Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000374 in 1,607,292 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 Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00053 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00036 (0 hom.)
• Consequence: CACNA1A NM_001127222.2 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:5
• Conservation: PhyloP100: 0.273

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 19-13286747-G-A is Benign according to our data. Variant chr19-13286747-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 195472.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Benign=3, Uncertain_significance=1}.
• BP7: Synonymous conserved (PhyloP=0.273 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.000525 (80/152282) while in subpopulation AFR AF= 0.000987 (41/41546). AF 95% confidence interval is 0.000747. There are 0 homozygotes in gnomad4. There are 40 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 80 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1A	NM_001127222.2	c.3309C>T	p.Pro1103Pro	synonymous_variant	Exon 20 of 47	ENST00000360228.11	NP_001120694.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CACNA1A	ENST00000360228.11	c.3309C>T	p.Pro1103Pro	synonymous_variant	Exon 20 of 47	1	NM_001127222.2	ENSP00000353362.5
CACNA1A	ENST00000638029.1	c.3321C>T	p.Pro1107Pro	synonymous_variant	Exon 20 of 48	5		ENSP00000489829.1
CACNA1A	ENST00000573710.7	c.3315C>T	p.Pro1105Pro	synonymous_variant	Exon 20 of 47	5		ENSP00000460092.3
CACNA1A	ENST00000635727.1	c.3312C>T	p.Pro1104Pro	synonymous_variant	Exon 20 of 47	5		ENSP00000490001.1
CACNA1A	ENST00000637769.1	c.3312C>T	p.Pro1104Pro	synonymous_variant	Exon 20 of 47	1		ENSP00000489778.1
CACNA1A	ENST00000636012.1	c.3312C>T	p.Pro1104Pro	synonymous_variant	Exon 20 of 46	5		ENSP00000490223.1
CACNA1A	ENST00000637736.1	c.3171C>T	p.Pro1057Pro	synonymous_variant	Exon 19 of 46	5		ENSP00000489861.1
CACNA1A	ENST00000636389.1	c.3312C>T	p.Pro1104Pro	synonymous_variant	Exon 20 of 47	5		ENSP00000489992.1
CACNA1A	ENST00000637432.1	c.3321C>T	p.Pro1107Pro	synonymous_variant	Exon 20 of 48	5		ENSP00000490617.1
CACNA1A	ENST00000636549.1	c.3312C>T	p.Pro1104Pro	synonymous_variant	Exon 20 of 48	5		ENSP00000490578.1
CACNA1A	ENST00000637927.1	c.3315C>T	p.Pro1105Pro	synonymous_variant	Exon 20 of 47	5		ENSP00000489715.1
CACNA1A	ENST00000635895.1	c.3312C>T	p.Pro1104Pro	synonymous_variant	Exon 20 of 47	5		ENSP00000490323.1
CACNA1A	ENST00000638009.2	c.3312C>T	p.Pro1104Pro	synonymous_variant	Exon 20 of 47	1		ENSP00000489913.1
CACNA1A	ENST00000637276.1	c.3312C>T	p.Pro1104Pro	synonymous_variant	Exon 20 of 46	5		ENSP00000489777.1

Frequencies

GnomAD3 genomes AF: 0.000526 AC: 80 AN: 152164 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.000990

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00103

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000382

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000463 AC: 111 AN: 239602 Hom.: 0 AF XY: 0.000474 AC XY: 62 AN XY: 130816

Gnomad AFR exome AF: 0.00109

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000331

Gnomad FIN exome AF: 0.00174

Gnomad NFE exome AF: 0.000463

Gnomad OTH exome AF: 0.000171

GnomAD4 exome AF: 0.000358 AC: 521 AN: 1455010 Hom.: 0 Cov.: 35 AF XY: 0.000358 AC XY: 259 AN XY: 723254

Gnomad4 AFR exome AF: 0.00114

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000198

Gnomad4 FIN exome AF: 0.00139

Gnomad4 NFE exome AF: 0.000327

Gnomad4 OTH exome AF: 0.000532

GnomAD4 genome AF: 0.000525 AC: 80 AN: 152282 Hom.: 0 Cov.: 31 AF XY: 0.000537 AC XY: 40 AN XY: 74460

Gnomad4 AFR AF: 0.000987

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000415

Gnomad4 FIN AF: 0.00103

Gnomad4 NFE AF: 0.000382

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000404 Hom.: 0

Bravo AF: 0.000521

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:5

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:2

May 19, 2014

Eurofins Ntd Llc (ga)

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 19, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

CACNA1A: BP4, BP7, BS1 -

not specified Benign:1

Apr 25, 2017

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

Dec 30, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Inborn genetic diseases Benign:1

Apr 03, 2019

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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	-0.83
CADD	Benign	3.1
DANN	Benign	0.69

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: rs374749004; hg19: chr19-13397561;