rs16012

Variant names:

• chr19-13308421-G-C
• rs16012
• NM_001127222.2:c.1776C>G

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_001127222.2(CACNA1A):​c.1776C>G​(p.Val592Val) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.018 in 1,609,264 control chromosomes in the GnomAD database, including 358 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.012 (17 hom., cov: 31)
  • Exomes 𝑓: 0.019 (341 hom.)
• Consequence: CACNA1A NM_001127222.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 1.24
• Publications: 7 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

ENSG00000306107 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.38).
• BP6: Variant 19-13308421-G-C is Benign according to our data. Variant chr19-13308421-G-C is described in ClinVar as Benign. ClinVar VariationId is 128545.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=1.24 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0118 (1799/152154) while in subpopulation NFE AF = 0.0208 (1417/68002). AF 95% confidence interval is 0.0199. There are 17 homozygotes in GnomAd4. There are 802 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High AC in GnomAd4 at 1799 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1A	NM_001127222.2	c.1776C>G	p.Val592Val	synonymous_variant	Exon 13 of 47	ENST00000360228.11	NP_001120694.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CACNA1A	ENST00000360228.11	c.1776C>G	p.Val592Val	synonymous_variant	Exon 13 of 47	1	NM_001127222.2	ENSP00000353362.5
CACNA1A	ENST00000638029.1	c.1779C>G	p.Val593Val	synonymous_variant	Exon 13 of 48	5		ENSP00000489829.1
CACNA1A	ENST00000573710.7	c.1782C>G	p.Val594Val	synonymous_variant	Exon 13 of 47	5		ENSP00000460092.3
CACNA1A	ENST00000635727.1	c.1779C>G	p.Val593Val	synonymous_variant	Exon 13 of 47	5		ENSP00000490001.1
CACNA1A	ENST00000637769.1	c.1779C>G	p.Val593Val	synonymous_variant	Exon 13 of 47	1		ENSP00000489778.1
CACNA1A	ENST00000636012.1	c.1779C>G	p.Val593Val	synonymous_variant	Exon 13 of 46	5		ENSP00000490223.1
CACNA1A	ENST00000637736.1	c.1638C>G	p.Val546Val	synonymous_variant	Exon 12 of 46	5		ENSP00000489861.1
CACNA1A	ENST00000636389.1	c.1779C>G	p.Val593Val	synonymous_variant	Exon 13 of 47	5		ENSP00000489992.1
CACNA1A	ENST00000637432.1	c.1779C>G	p.Val593Val	synonymous_variant	Exon 13 of 48	5		ENSP00000490617.1
CACNA1A	ENST00000636549.1	c.1779C>G	p.Val593Val	synonymous_variant	Exon 13 of 48	5		ENSP00000490578.1
CACNA1A	ENST00000637927.1	c.1782C>G	p.Val594Val	synonymous_variant	Exon 13 of 47	5		ENSP00000489715.1
CACNA1A	ENST00000635895.1	c.1779C>G	p.Val593Val	synonymous_variant	Exon 13 of 47	5		ENSP00000490323.1
CACNA1A	ENST00000638009.2	c.1779C>G	p.Val593Val	synonymous_variant	Exon 13 of 47	1		ENSP00000489913.1
CACNA1A	ENST00000637276.1	c.1779C>G	p.Val593Val	synonymous_variant	Exon 13 of 46	5		ENSP00000489777.1
CACNA1A	ENST00000636768.2	n.1779C>G		non_coding_transcript_exon_variant	Exon 13 of 45	5		ENSP00000490190.2
CACNA1A	ENST00000713789.1	n.1776C>G		non_coding_transcript_exon_variant	Exon 13 of 47			ENSP00000519091.1

Frequencies

GnomAD3 genomes AF: 0.0118 AC: 1799 AN: 152036 Hom.: 17 Cov.: 31

Gnomad AFR AF: 0.00324

Gnomad AMI AF: 0.00440

Gnomad AMR AF: 0.00576

Gnomad ASJ AF: 0.0113

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00249

Gnomad FIN AF: 0.00822

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0208

Gnomad OTH AF: 0.00862

GnomAD2 exomes AF: 0.0112 AC: 2756 AN: 247170 AF XY: 0.0111

Gnomad AFR exome AF: 0.00331

Gnomad AMR exome AF: 0.00481

Gnomad ASJ exome AF: 0.0101

Gnomad EAS exome AF: 0.0000558

Gnomad FIN exome AF: 0.00801

Gnomad NFE exome AF: 0.0191

Gnomad OTH exome AF: 0.0101

GnomAD4 exome AF: 0.0186 AC: 27112 AN: 1457110 Hom.: 341 Cov.: 31 AF XY: 0.0181 AC XY: 13100 AN XY: 724848

African (AFR) AF: 0.00272 AC: 91 AN: 33400

American (AMR) AF: 0.00512 AC: 228 AN: 44568

Ashkenazi Jewish (ASJ) AF: 0.0109 AC: 284 AN: 26016

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39648

South Asian (SAS) AF: 0.00238 AC: 204 AN: 85716

European-Finnish (FIN) AF: 0.00859 AC: 458 AN: 53296

Middle Eastern (MID) AF: 0.00193 AC: 11 AN: 5696

European-Non Finnish (NFE) AF: 0.0225 AC: 24959 AN: 1108526

Other (OTH) AF: 0.0145 AC: 875 AN: 60244

GnomAD4 genome AF: 0.0118 AC: 1799 AN: 152154 Hom.: 17 Cov.: 31 AF XY: 0.0108 AC XY: 802 AN XY: 74386

African (AFR) AF: 0.00323 AC: 134 AN: 41502

American (AMR) AF: 0.00576 AC: 88 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.0113 AC: 39 AN: 3464

East Asian (EAS) AF: 0.00 AC: 0 AN: 5172

South Asian (SAS) AF: 0.00249 AC: 12 AN: 4824

European-Finnish (FIN) AF: 0.00822 AC: 87 AN: 10588

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0208 AC: 1417 AN: 68002

Other (OTH) AF: 0.00853 AC: 18 AN: 2110

Alfa AF: 0.0164 Hom.: 2

Bravo AF: 0.0114

Asia WGS AF: 0.00260 AC: 9 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:6

-

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. -

Jan 11, 2016

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. -

-

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not provided Benign:2

-

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

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

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Inborn genetic diseases Benign:1

Jun 18, 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.38
CADD	Benign	12
DANN	Benign	0.86
PhyloP100		1.2
Mutation Taster		=91/9	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: rs16012; hg19: chr19-13419235;