19-13277090-A-G

Variant names:

• chr19-13277090-A-G
• rs16030
• NM_001127222.2:c.3861T>C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_023035.3(CACNA1A):​c.3873T>C​(p.Phe1291Phe) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.212 in 1,608,954 control chromosomes in the GnomAD database, including 37,769 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.18 (2720 hom., cov: 31)
  • Exomes 𝑓: 0.22 (35049 hom.)
• Consequence: CACNA1A NM_023035.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: 0.776
• Publications: 15 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=-0.53).
• BP6: Variant 19-13277090-A-G is Benign according to our data. Variant chr19-13277090-A-G is described in ClinVar as Benign. ClinVar VariationId is 128553.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.776 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.222 is higher than 0.05.

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.3861T>C	p.Phe1287Phe	synonymous	Exon 23 of 47	NP_001120694.1
	CACNA1A	NM_001127221.2	MANE Plus Clinical	c.3864T>C	p.Phe1288Phe	synonymous	Exon 23 of 47	NP_001120693.1
	CACNA1A	NM_023035.3		c.3873T>C	p.Phe1291Phe	synonymous	Exon 23 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.3861T>C	p.Phe1287Phe	synonymous	Exon 23 of 47	ENSP00000353362.5
	CACNA1A	ENST00000638009.2	TSL:1 MANE Plus Clinical	c.3864T>C	p.Phe1288Phe	synonymous	Exon 23 of 47	ENSP00000489913.1
	CACNA1A	ENST00000638029.1	TSL:5	c.3873T>C	p.Phe1291Phe	synonymous	Exon 23 of 48	ENSP00000489829.1

Frequencies

GnomAD3 genomes AF: 0.177 AC: 26980 AN: 152008 Hom.: 2715 Cov.: 31

Gnomad AFR AF: 0.0947

Gnomad AMI AF: 0.0947

Gnomad AMR AF: 0.164

Gnomad ASJ AF: 0.182

Gnomad EAS AF: 0.121

Gnomad SAS AF: 0.220

Gnomad FIN AF: 0.223

Gnomad MID AF: 0.168

Gnomad NFE AF: 0.225

Gnomad OTH AF: 0.199

GnomAD2 exomes AF: 0.195 AC: 48395 AN: 248210 AF XY: 0.201

Gnomad AFR exome AF: 0.0946

Gnomad AMR exome AF: 0.162

Gnomad ASJ exome AF: 0.195

Gnomad EAS exome AF: 0.111

Gnomad FIN exome AF: 0.218

Gnomad NFE exome AF: 0.220

Gnomad OTH exome AF: 0.208

GnomAD4 exome AF: 0.216 AC: 314386 AN: 1456828 Hom.: 35049 Cov.: 30 AF XY: 0.217 AC XY: 157645 AN XY: 724870

African (AFR) AF: 0.0891 AC: 2976 AN: 33406

American (AMR) AF: 0.169 AC: 7558 AN: 44610

Ashkenazi Jewish (ASJ) AF: 0.194 AC: 5069 AN: 26074

East Asian (EAS) AF: 0.126 AC: 4997 AN: 39638

South Asian (SAS) AF: 0.226 AC: 19435 AN: 86094

European-Finnish (FIN) AF: 0.218 AC: 11590 AN: 53246

Middle Eastern (MID) AF: 0.195 AC: 1124 AN: 5760

European-Non Finnish (NFE) AF: 0.225 AC: 249347 AN: 1107812

Other (OTH) AF: 0.204 AC: 12290 AN: 60188

GnomAD4 genome AF: 0.178 AC: 27010 AN: 152126 Hom.: 2720 Cov.: 31 AF XY: 0.177 AC XY: 13150 AN XY: 74360

African (AFR) AF: 0.0948 AC: 3934 AN: 41516

American (AMR) AF: 0.164 AC: 2514 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.182 AC: 632 AN: 3468

East Asian (EAS) AF: 0.121 AC: 627 AN: 5174

South Asian (SAS) AF: 0.221 AC: 1067 AN: 4820

European-Finnish (FIN) AF: 0.223 AC: 2359 AN: 10576

Middle Eastern (MID) AF: 0.163 AC: 48 AN: 294

European-Non Finnish (NFE) AF: 0.225 AC: 15315 AN: 67968

Other (OTH) AF: 0.202 AC: 428 AN: 2116

Alfa AF: 0.208 Hom.: 8907

Bravo AF: 0.169

Asia WGS AF: 0.184 AC: 636 AN: 3478

EpiCase AF: 0.220

EpiControl AF: 0.221

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	8	not specified (8)
-	-	1	Episodic ataxia type 2;C4310716:Developmental and epileptic encephalopathy, 42 (1)
-	-	1	Inborn genetic diseases (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.53
CADD	Benign	9.0
DANN	Benign	0.73
PhyloP100		0.78
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
Splicevardb		1.0
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: rs16030; hg19: chr19-13387904; COSMIC: COSV64192867;