19-13212447-C-T

Variant names:

• chr19-13212447-C-T
• rs7249722
• NM_001127222.2:c.6126G>A

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.6126G>A​(p.Thr2042Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0014 in 1,611,078 control chromosomes in the GnomAD database, including 25 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0071 (9 hom., cov: 32)
  • Exomes 𝑓: 0.00080 (16 hom.)
• Consequence: CACNA1A NM_001127222.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -4.21
• Publications: 3 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

ENSG00000300728 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.69).
• BP6: Variant 19-13212447-C-T is Benign according to our data. Variant chr19-13212447-C-T is described in ClinVar as [Benign]. Clinvar id is 382860.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-4.22 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00712 (1084/152262) while in subpopulation AFR AF = 0.025 (1039/41532). AF 95% confidence interval is 0.0238. There are 9 homozygotes in GnomAd4. There are 514 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 1084 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1A	NM_001127222.2	c.6126G>A	p.Thr2042Thr	synonymous_variant	Exon 42 of 47	ENST00000360228.11	NP_001120694.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CACNA1A	ENST00000360228.11	c.6126G>A	p.Thr2042Thr	synonymous_variant	Exon 42 of 47	1	NM_001127222.2	ENSP00000353362.5
CACNA1A	ENST00000638029.1	c.6144G>A	p.Thr2048Thr	synonymous_variant	Exon 43 of 48	5		ENSP00000489829.1
CACNA1A	ENST00000573710.7	c.6132G>A	p.Thr2044Thr	synonymous_variant	Exon 42 of 47	5		ENSP00000460092.3
CACNA1A	ENST00000635727.1	c.6129G>A	p.Thr2043Thr	synonymous_variant	Exon 42 of 47	5		ENSP00000490001.1
CACNA1A	ENST00000637769.1	c.6129G>A	p.Thr2043Thr	synonymous_variant	Exon 42 of 47	1		ENSP00000489778.1
CACNA1A	ENST00000636012.1	c.6129G>A	p.Thr2043Thr	synonymous_variant	Exon 42 of 46	5		ENSP00000490223.1
CACNA1A	ENST00000637736.1	c.5988G>A	p.Thr1996Thr	synonymous_variant	Exon 41 of 46	5		ENSP00000489861.1
CACNA1A	ENST00000636389.1	c.6129G>A	p.Thr2043Thr	synonymous_variant	Exon 42 of 47	5		ENSP00000489992.1
CACNA1A	ENST00000637432.1	c.6144G>A	p.Thr2048Thr	synonymous_variant	Exon 43 of 48	5		ENSP00000490617.1
CACNA1A	ENST00000636549.1	c.6135G>A	p.Thr2045Thr	synonymous_variant	Exon 43 of 48	5		ENSP00000490578.1
CACNA1A	ENST00000637927.1	c.6132G>A	p.Thr2044Thr	synonymous_variant	Exon 42 of 47	5		ENSP00000489715.1
CACNA1A	ENST00000635895.1	c.6129G>A	p.Thr2043Thr	synonymous_variant	Exon 42 of 47	5		ENSP00000490323.1
CACNA1A	ENST00000638009.2	c.6129G>A	p.Thr2043Thr	synonymous_variant	Exon 42 of 47	1		ENSP00000489913.1
CACNA1A	ENST00000637276.1	c.6129G>A	p.Thr2043Thr	synonymous_variant	Exon 42 of 46	5		ENSP00000489777.1
CACNA1A	ENST00000636768.2	n.*428G>A		non_coding_transcript_exon_variant	Exon 41 of 45	5		ENSP00000490190.2
CACNA1A	ENST00000713789.1	n.*1341G>A		non_coding_transcript_exon_variant	Exon 43 of 47			ENSP00000519091.1
CACNA1A	ENST00000636768.2	n.*428G>A		3_prime_UTR_variant	Exon 41 of 45	5		ENSP00000490190.2
CACNA1A	ENST00000713789.1	n.*1341G>A		3_prime_UTR_variant	Exon 43 of 47			ENSP00000519091.1

Frequencies

GnomAD3 genomes AF: 0.00711 AC: 1082 AN: 152144 Hom.: 8 Cov.: 32

Gnomad AFR AF: 0.0250

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00196

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0000882

Gnomad OTH AF: 0.00335

GnomAD2 exomes AF: 0.00190 AC: 457 AN: 240830 AF XY: 0.00154

Gnomad AFR exome AF: 0.0265

Gnomad AMR exome AF: 0.00131

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000128

Gnomad OTH exome AF: 0.00102

GnomAD4 exome AF: 0.000801 AC: 1168 AN: 1458816 Hom.: 16 Cov.: 34 AF XY: 0.000743 AC XY: 539 AN XY: 725426

African (AFR) AF: 0.0260 AC: 869 AN: 33442

American (AMR) AF: 0.00141 AC: 62 AN: 44104

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26030

East Asian (EAS) AF: 0.0000505 AC: 2 AN: 39572

South Asian (SAS) AF: 0.000128 AC: 11 AN: 85668

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53162

Middle Eastern (MID) AF: 0.00399 AC: 23 AN: 5764

European-Non Finnish (NFE) AF: 0.0000630 AC: 70 AN: 1110802

Other (OTH) AF: 0.00217 AC: 131 AN: 60272

GnomAD4 genome AF: 0.00712 AC: 1084 AN: 152262 Hom.: 9 Cov.: 32 AF XY: 0.00690 AC XY: 514 AN XY: 74446

African (AFR) AF: 0.0250 AC: 1039 AN: 41532

American (AMR) AF: 0.00196 AC: 30 AN: 15302

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

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

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.0000882 AC: 6 AN: 68002

Other (OTH) AF: 0.00331 AC: 7 AN: 2112

Alfa AF: 0.00302 Hom.: 11

Bravo AF: 0.00813

Asia WGS AF: 0.00375 AC: 13 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Feb 23, 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. -

-

Genome Diagnostics Laboratory, University Medical Center Utrecht

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

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Sep 28, 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

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 21, 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. -

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	-0.69
CADD	Benign	0.33
DANN	Benign	0.68
PhyloP100		-4.2
Mutation Taster		=88/12	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: rs7249722; hg19: chr19-13323261;