rs16059

Variant names:

• chr19-13207403-G-A
• rs16059
• NM_001127222.2:c.7431C>T

Your query was ambiguous. Multiple possible variants found:

• chr19-13207403-G-A
• chr19-13207403-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_023035.3(CACNA1A):​c.7449C>T​(p.Tyr2483Tyr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00841 in 1,535,954 control chromosomes in the GnomAD database, including 114 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0074 (11 hom., cov: 31)
  • Exomes 𝑓: 0.0085 (103 hom.)
• Consequence: CACNA1A NM_023035.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.150
• Publications: 2 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=-0.65).
• BP6: Variant 19-13207403-G-A is Benign according to our data. Variant chr19-13207403-G-A is described in ClinVar as Benign. ClinVar VariationId is 257513.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.15 with no splicing effect.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00737 (1118/151678) while in subpopulation AMR AF = 0.0202 (308/15244). AF 95% confidence interval is 0.0183. There are 11 homozygotes in GnomAd4. There are 580 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High AC in GnomAd4 at 1118 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_023035.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CACNA1A	NM_001127222.2	MANE Select	c.7431C>T	p.Tyr2477Tyr	synonymous	Exon 47 of 47	NP_001120694.1
	CACNA1A	NM_001127221.2	MANE Plus Clinical	c.*643C>T		3_prime_UTR	Exon 47 of 47	NP_001120693.1
	CACNA1A	NM_023035.3		c.7449C>T	p.Tyr2483Tyr	synonymous	Exon 48 of 48	NP_075461.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CACNA1A	ENST00000360228.11	TSL:1 MANE Select	c.7431C>T	p.Tyr2477Tyr	synonymous	Exon 47 of 47	ENSP00000353362.5
	CACNA1A	ENST00000638029.1	TSL:5	c.7449C>T	p.Tyr2483Tyr	synonymous	Exon 48 of 48	ENSP00000489829.1
	CACNA1A	ENST00000573710.7	TSL:5	c.7437C>T	p.Tyr2479Tyr	synonymous	Exon 47 of 47	ENSP00000460092.3

Frequencies

GnomAD3 genomes AF: 0.00734 AC: 1113 AN: 151570 Hom.: 10 Cov.: 31

Gnomad AFR AF: 0.00182

Gnomad AMI AF: 0.0399

Gnomad AMR AF: 0.0201

Gnomad ASJ AF: 0.000289

Gnomad EAS AF: 0.00934

Gnomad SAS AF: 0.00994

Gnomad FIN AF: 0.00619

Gnomad MID AF: 0.00318

Gnomad NFE AF: 0.00757

Gnomad OTH AF: 0.00961

GnomAD2 exomes AF: 0.0126 AC: 1749 AN: 139132 AF XY: 0.0116

Gnomad AFR exome AF: 0.00133

Gnomad AMR exome AF: 0.0327

Gnomad ASJ exome AF: 0.000122

Gnomad EAS exome AF: 0.0144

Gnomad FIN exome AF: 0.00760

Gnomad NFE exome AF: 0.00749

Gnomad OTH exome AF: 0.0118

GnomAD4 exome AF: 0.00852 AC: 11793 AN: 1384276 Hom.: 103 Cov.: 30 AF XY: 0.00864 AC XY: 5916 AN XY: 685000

African (AFR) AF: 0.00136 AC: 42 AN: 30914

American (AMR) AF: 0.0312 AC: 1133 AN: 36344

Ashkenazi Jewish (ASJ) AF: 0.000323 AC: 8 AN: 24778

East Asian (EAS) AF: 0.0101 AC: 358 AN: 35486

South Asian (SAS) AF: 0.0104 AC: 832 AN: 80028

European-Finnish (FIN) AF: 0.00853 AC: 295 AN: 34598

Middle Eastern (MID) AF: 0.00373 AC: 21 AN: 5632

European-Non Finnish (NFE) AF: 0.00801 AC: 8641 AN: 1078958

Other (OTH) AF: 0.00805 AC: 463 AN: 57538

GnomAD4 genome AF: 0.00737 AC: 1118 AN: 151678 Hom.: 11 Cov.: 31 AF XY: 0.00782 AC XY: 580 AN XY: 74164

African (AFR) AF: 0.00179 AC: 74 AN: 41432

American (AMR) AF: 0.0202 AC: 308 AN: 15244

Ashkenazi Jewish (ASJ) AF: 0.000289 AC: 1 AN: 3460

East Asian (EAS) AF: 0.00937 AC: 48 AN: 5122

South Asian (SAS) AF: 0.00974 AC: 47 AN: 4826

European-Finnish (FIN) AF: 0.00619 AC: 65 AN: 10502

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

European-Non Finnish (NFE) AF: 0.00757 AC: 513 AN: 67794

Other (OTH) AF: 0.0119 AC: 25 AN: 2104

Alfa AF: 0.00610 Hom.: 1

Bravo AF: 0.00870

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	3	not specified (3)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.65
CADD	Benign	6.4
DANN	Benign	0.97
PhyloP100		0.15
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: rs16059; hg19: chr19-13318217;