rs16021

Variant names:

• chr19-13298894-G-A
• rs16021
• NM_001127222.2:c.2739C>T

Your query was ambiguous. Multiple possible variants found:

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

Variant summary

Our verdict is Benign. The variant received -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 (★★). Synonymous variant affecting the same amino acid position (i.e. P913P) has been classified as Likely 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
• Publications: 0 publications found

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 Gene-Disease associations (from GenCC):

• episodic ataxia type 2

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Ambry Genetics, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
• undetermined early-onset epileptic encephalopathy

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, Illumina
• developmental and epileptic encephalopathy, 42

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• migraine, familial hemiplegic, 1

  Inheritance: AD Classification: STRONG Submitted by: Ambry Genetics, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
• spinocerebellar ataxia type 6

  Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Ambry Genetics, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Orphanet
• benign paroxysmal torticollis of infancy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• familial or sporadic hemiplegic migraine

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Lennox-Gastaut syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -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.
• 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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 896 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1A	NM_001127222.2	c.2739C>T	p.Pro913Pro	synonymous_variant	Exon 19 of 47	ENST00000360228.11	NP_001120694.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CACNA1A	ENST00000360228.11	c.2739C>T	p.Pro913Pro	synonymous_variant	Exon 19 of 47	1	NM_001127222.2	ENSP00000353362.5
CACNA1A	ENST00000638029.1	c.2751C>T	p.Pro917Pro	synonymous_variant	Exon 19 of 48	5		ENSP00000489829.1
CACNA1A	ENST00000573710.7	c.2745C>T	p.Pro915Pro	synonymous_variant	Exon 19 of 47	5		ENSP00000460092.3
CACNA1A	ENST00000635727.1	c.2742C>T	p.Pro914Pro	synonymous_variant	Exon 19 of 47	5		ENSP00000490001.1
CACNA1A	ENST00000637769.1	c.2742C>T	p.Pro914Pro	synonymous_variant	Exon 19 of 47	1		ENSP00000489778.1
CACNA1A	ENST00000636012.1	c.2742C>T	p.Pro914Pro	synonymous_variant	Exon 19 of 46	5		ENSP00000490223.1
CACNA1A	ENST00000637736.1	c.2601C>T	p.Pro867Pro	synonymous_variant	Exon 18 of 46	5		ENSP00000489861.1
CACNA1A	ENST00000636389.1	c.2742C>T	p.Pro914Pro	synonymous_variant	Exon 19 of 47	5		ENSP00000489992.1
CACNA1A	ENST00000637432.1	c.2751C>T	p.Pro917Pro	synonymous_variant	Exon 19 of 48	5		ENSP00000490617.1
CACNA1A	ENST00000636549.1	c.2742C>T	p.Pro914Pro	synonymous_variant	Exon 19 of 48	5		ENSP00000490578.1
CACNA1A	ENST00000637927.1	c.2745C>T	p.Pro915Pro	synonymous_variant	Exon 19 of 47	5		ENSP00000489715.1
CACNA1A	ENST00000635895.1	c.2742C>T	p.Pro914Pro	synonymous_variant	Exon 19 of 47	5		ENSP00000490323.1
CACNA1A	ENST00000638009.2	c.2742C>T	p.Pro914Pro	synonymous_variant	Exon 19 of 47	1		ENSP00000489913.1
CACNA1A	ENST00000637276.1	c.2742C>T	p.Pro914Pro	synonymous_variant	Exon 19 of 46	5		ENSP00000489777.1
CACNA1A	ENST00000636768.2	n.2742C>T		non_coding_transcript_exon_variant	Exon 19 of 45	5		ENSP00000490190.2
CACNA1A	ENST00000713789.1	n.2739C>T		non_coding_transcript_exon_variant	Exon 19 of 47			ENSP00000519091.1

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

GnomAD2 exomes AF: 0.00134 AC: 292 AN: 218572 AF XY: 0.000936

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 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

African (AFR) AF: 0.0203 AC: 674 AN: 33214

American (AMR) AF: 0.000744 AC: 33 AN: 44374

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25956

East Asian (EAS) AF: 0.00 AC: 0 AN: 39492

South Asian (SAS) AF: 0.0000584 AC: 5 AN: 85544

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 38246

Middle Eastern (MID) AF: 0.000726 AC: 4 AN: 5510

European-Non Finnish (NFE) AF: 0.0000306 AC: 34 AN: 1109828

Other (OTH) AF: 0.00103 AC: 62 AN: 60010

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

African (AFR) AF: 0.0204 AC: 848 AN: 41574

American (AMR) AF: 0.00216 AC: 33 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

Middle Eastern (MID) AF: 0.00342 AC: 1 AN: 292

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 68022

Other (OTH) AF: 0.00473 AC: 10 AN: 2116

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

Jun 12, 2015

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 26, 2020

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 01, 2017

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

-

Genetic Services Laboratory, University of Chicago

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

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

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Inborn genetic diseases Benign:1

Jun 27, 2016

Ambry Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

CACNA1A-related disorder Benign:1

Jun 14, 2019

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

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
PhyloP100		-2.6
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs16021; hg19: chr19-13409708;