rs16011

Variant names:

• chr19-13312711-C-T
• rs16011
• NM_001127222.2:c.1626G>A

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_001127222.2(CACNA1A):​c.1626G>A​(p.Thr542Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00623 in 1,592,302 control chromosomes in the GnomAD database, including 470 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.034 (265 hom., cov: 32)
  • Exomes 𝑓: 0.0033 (205 hom.)
• Consequence: CACNA1A NM_001127222.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -0.513
• Publications: 4 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=-0.28).
• BP6: Variant 19-13312711-C-T is Benign according to our data. Variant chr19-13312711-C-T is described in ClinVar as [Benign]. Clinvar id is 128544.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.513 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.113 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1A	NM_001127222.2	c.1626G>A	p.Thr542Thr	synonymous_variant	Exon 12 of 47	ENST00000360228.11	NP_001120694.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CACNA1A	ENST00000360228.11	c.1626G>A	p.Thr542Thr	synonymous_variant	Exon 12 of 47	1	NM_001127222.2	ENSP00000353362.5
CACNA1A	ENST00000638029.1	c.1629G>A	p.Thr543Thr	synonymous_variant	Exon 12 of 48	5		ENSP00000489829.1
CACNA1A	ENST00000573710.7	c.1632G>A	p.Thr544Thr	synonymous_variant	Exon 12 of 47	5		ENSP00000460092.3
CACNA1A	ENST00000635727.1	c.1629G>A	p.Thr543Thr	synonymous_variant	Exon 12 of 47	5		ENSP00000490001.1
CACNA1A	ENST00000637769.1	c.1629G>A	p.Thr543Thr	synonymous_variant	Exon 12 of 47	1		ENSP00000489778.1
CACNA1A	ENST00000636012.1	c.1629G>A	p.Thr543Thr	synonymous_variant	Exon 12 of 46	5		ENSP00000490223.1
CACNA1A	ENST00000637736.1	c.1488G>A	p.Thr496Thr	synonymous_variant	Exon 11 of 46	5		ENSP00000489861.1
CACNA1A	ENST00000636389.1	c.1629G>A	p.Thr543Thr	synonymous_variant	Exon 12 of 47	5		ENSP00000489992.1
CACNA1A	ENST00000637432.1	c.1629G>A	p.Thr543Thr	synonymous_variant	Exon 12 of 48	5		ENSP00000490617.1
CACNA1A	ENST00000636549.1	c.1629G>A	p.Thr543Thr	synonymous_variant	Exon 12 of 48	5		ENSP00000490578.1
CACNA1A	ENST00000637927.1	c.1632G>A	p.Thr544Thr	synonymous_variant	Exon 12 of 47	5		ENSP00000489715.1
CACNA1A	ENST00000635895.1	c.1629G>A	p.Thr543Thr	synonymous_variant	Exon 12 of 47	5		ENSP00000490323.1
CACNA1A	ENST00000638009.2	c.1629G>A	p.Thr543Thr	synonymous_variant	Exon 12 of 47	1		ENSP00000489913.1
CACNA1A	ENST00000637276.1	c.1629G>A	p.Thr543Thr	synonymous_variant	Exon 12 of 46	5		ENSP00000489777.1
CACNA1A	ENST00000636768.2	n.1629G>A		non_coding_transcript_exon_variant	Exon 12 of 45	5		ENSP00000490190.2
CACNA1A	ENST00000713789.1	n.1626G>A		non_coding_transcript_exon_variant	Exon 12 of 47			ENSP00000519091.1

Frequencies

GnomAD3 genomes AF: 0.0337 AC: 5129 AN: 152072 Hom.: 266 Cov.: 32

Gnomad AFR AF: 0.116

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0153

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.000830

Gnomad FIN AF: 0.0000944

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.000691

Gnomad OTH AF: 0.0239

GnomAD2 exomes AF: 0.00820 AC: 1881 AN: 229476 AF XY: 0.00622

Gnomad AFR exome AF: 0.116

Gnomad AMR exome AF: 0.00579

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000476

Gnomad OTH exome AF: 0.00478

GnomAD4 exome AF: 0.00331 AC: 4773 AN: 1440112 Hom.: 205 Cov.: 29 AF XY: 0.00286 AC XY: 2050 AN XY: 716140

African (AFR) AF: 0.112 AC: 3541 AN: 31656

American (AMR) AF: 0.00649 AC: 260 AN: 40086

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25684

East Asian (EAS) AF: 0.00 AC: 0 AN: 38280

South Asian (SAS) AF: 0.000245 AC: 20 AN: 81792

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53222

Middle Eastern (MID) AF: 0.00699 AC: 40 AN: 5722

European-Non Finnish (NFE) AF: 0.000405 AC: 447 AN: 1104088

Other (OTH) AF: 0.00780 AC: 465 AN: 59582

GnomAD4 genome AF: 0.0338 AC: 5151 AN: 152190 Hom.: 265 Cov.: 32 AF XY: 0.0321 AC XY: 2385 AN XY: 74396

African (AFR) AF: 0.116 AC: 4811 AN: 41490

American (AMR) AF: 0.0153 AC: 234 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5186

South Asian (SAS) AF: 0.000831 AC: 4 AN: 4816

European-Finnish (FIN) AF: 0.0000944 AC: 1 AN: 10596

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.000691 AC: 47 AN: 68026

Other (OTH) AF: 0.0237 AC: 50 AN: 2112

Alfa AF: 0.0192 Hom.: 62

Bravo AF: 0.0384

Asia WGS AF: 0.0100 AC: 36 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

-

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

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

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 23, 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. -

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 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Inborn genetic diseases Benign:1

Apr 15, 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	-0.28
CADD	Benign	8.3
DANN	Benign	0.72
PhyloP100		-0.51
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs16011; hg19: chr19-13423525; COSMIC: COSV64197517; COSMIC: COSV64197517;