rs16021

Positions:

• chr19-13298894-G-A
• chr19-13298894-G-C

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.2739C>T​(p.Pro913Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00107 in 1,594,498 control chromosomes in the GnomAD database, including 14 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0059 (5 hom., cov: 32)
  • Exomes 𝑓: 0.00056 (9 hom.)
• Consequence: CACNA1A NM_001127222.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -2.64

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=-0.82).
• BP6: Variant 19-13298894-G-A is Benign according to our data. Variant chr19-13298894-G-A is described in ClinVar as [Benign]. Clinvar id is 128549.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-13298894-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-2.64 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00588 (896/152324) while in subpopulation AFR AF= 0.0204 (848/41574). AF 95% confidence interval is 0.0193. There are 5 homozygotes in gnomad4. There are 410 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 896 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CACNA1A	NM_001127222.2	c.2739C>T	p.Pro913Pro	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.2739C>T	p.Pro913Pro	synonymous_variant	19/47	1	NM_001127222.2	ENSP00000353362.5
CACNA1A	ENST00000638029.1	c.2751C>T	p.Pro917Pro	synonymous_variant	19/48	5		ENSP00000489829.1
CACNA1A	ENST00000573710.7	c.2745C>T	p.Pro915Pro	synonymous_variant	19/47	5		ENSP00000460092.3
CACNA1A	ENST00000635727.1	c.2742C>T	p.Pro914Pro	synonymous_variant	19/47	5		ENSP00000490001.1
CACNA1A	ENST00000637769.1	c.2742C>T	p.Pro914Pro	synonymous_variant	19/47	1		ENSP00000489778.1
CACNA1A	ENST00000636012.1	c.2742C>T	p.Pro914Pro	synonymous_variant	19/46	5		ENSP00000490223.1
CACNA1A	ENST00000637736.1	c.2601C>T	p.Pro867Pro	synonymous_variant	18/46	5		ENSP00000489861.1
CACNA1A	ENST00000636389.1	c.2742C>T	p.Pro914Pro	synonymous_variant	19/47	5		ENSP00000489992.1
CACNA1A	ENST00000637432.1	c.2751C>T	p.Pro917Pro	synonymous_variant	19/48	5		ENSP00000490617.1
CACNA1A	ENST00000636549.1	c.2742C>T	p.Pro914Pro	synonymous_variant	19/48	5		ENSP00000490578.1
CACNA1A	ENST00000637927.1	c.2745C>T	p.Pro915Pro	synonymous_variant	19/47	5		ENSP00000489715.1
CACNA1A	ENST00000635895.1	c.2742C>T	p.Pro914Pro	synonymous_variant	19/47	5		ENSP00000490323.1
CACNA1A	ENST00000638009.2	c.2742C>T	p.Pro914Pro	synonymous_variant	19/47	1		ENSP00000489913.1
CACNA1A	ENST00000637276.1	c.2742C>T	p.Pro914Pro	synonymous_variant	19/46	5		ENSP00000489777.1

Frequencies

GnomAD3 genomes AF: 0.00587 AC: 893 AN: 152216 Hom.: 5 Cov.: 32

Gnomad AFR AF: 0.0204

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00216

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00318

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00478

GnomAD3 exomes AF: 0.00134 AC: 292 AN: 218572 Hom.: 5 AF XY: 0.000936 AC XY: 114 AN XY: 121838

Gnomad AFR exome AF: 0.0202

Gnomad AMR exome AF: 0.000712

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000675

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000304

Gnomad OTH exome AF: 0.000722

GnomAD4 exome AF: 0.000563 AC: 812 AN: 1442174 Hom.: 9 Cov.: 32 AF XY: 0.000479 AC XY: 344 AN XY: 717764

Gnomad4 AFR exome AF: 0.0203

Gnomad4 AMR exome AF: 0.000744

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000584

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000306

Gnomad4 OTH exome AF: 0.00103

GnomAD4 genome AF: 0.00588 AC: 896 AN: 152324 Hom.: 5 Cov.: 32 AF XY: 0.00551 AC XY: 410 AN XY: 74476

Gnomad4 AFR AF: 0.0204

Gnomad4 AMR AF: 0.00216

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.00473

Alfa AF: 0.000308 Hom.: 1

Bravo AF: 0.00633

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Mar 26, 2020	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 01, 2017	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. -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jun 12, 2015	- -
Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -

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

Jun 27, 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

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

CACNA1A-related disorder Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 14, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	1.5
DANN	Benign	0.86

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: rs16021; hg19: chr19-13409708;