NM_001127222.2:c.*219A>C

Variant names:

• chr19-13207094-T-G
• rs116023034
• NM_001127222.2:c.*219A>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001127222.2(CACNA1A):​c.*219A>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0133 in 405,924 control chromosomes in the GnomAD database, including 135 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.019 (69 hom., cov: 27)
  • Exomes 𝑓: 0.010 (66 hom.)
• Consequence: CACNA1A NM_001127222.2 3_prime_UTR
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.214
• Publications: 0 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: Labcorp Genetics (formerly Invitae), Ambry Genetics, Genomics England PanelApp, Orphanet
• undetermined early-onset epileptic encephalopathy

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Illumina, Orphanet
• developmental and epileptic encephalopathy, 42

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics
• migraine, familial hemiplegic, 1

  Inheritance: AD Classification: STRONG Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), Genomics England PanelApp
• spinocerebellar ataxia type 6

  Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Ambry Genetics
• 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.93).
• BP6: Variant 19-13207094-T-G is Benign according to our data. Variant chr19-13207094-T-G is described in ClinVar as Likely_benign. ClinVar VariationId is 1208972.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0606 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001127222.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CACNA1A	NM_001127222.2	MANE Select	c.*219A>C		3_prime_UTR	Exon 47 of 47	NP_001120694.1	O00555-8
	CACNA1A	NM_001127221.2	MANE Plus Clinical	c.*952A>C		3_prime_UTR	Exon 47 of 47	NP_001120693.1	O00555-3
	CACNA1A	NM_023035.3		c.*219A>C		3_prime_UTR	Exon 48 of 48	NP_075461.2	A0A087WW63

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CACNA1A	ENST00000360228.11	TSL:1 MANE Select	c.*219A>C		3_prime_UTR	Exon 47 of 47	ENSP00000353362.5	O00555-8
	CACNA1A	ENST00000638009.2	TSL:1 MANE Plus Clinical	c.*952A>C		3_prime_UTR	Exon 47 of 47	ENSP00000489913.1	O00555-3
	CACNA1A	ENST00000637769.1	TSL:1	c.*219A>C		3_prime_UTR	Exon 47 of 47	ENSP00000489778.1	A0A1B0GTN7

Frequencies

GnomAD3 genomes AF: 0.0186 AC: 2814 AN: 151404 Hom.: 69 Cov.: 27

Gnomad AFR AF: 0.0468

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00631

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.0664

Gnomad SAS AF: 0.0535

Gnomad FIN AF: 0.0109

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.000663

Gnomad OTH AF: 0.0116

GnomAD4 exome AF: 0.0100 AC: 2556 AN: 254410 Hom.: 66 Cov.: 4 AF XY: 0.0110 AC XY: 1477 AN XY: 134698

African (AFR) AF: 0.0444 AC: 224 AN: 5050

American (AMR) AF: 0.00602 AC: 35 AN: 5810

Ashkenazi Jewish (ASJ) AF: 0.000915 AC: 7 AN: 7654

East Asian (EAS) AF: 0.0595 AC: 965 AN: 16220

South Asian (SAS) AF: 0.0341 AC: 760 AN: 22294

European-Finnish (FIN) AF: 0.00990 AC: 201 AN: 20304

Middle Eastern (MID) AF: 0.0154 AC: 18 AN: 1172

European-Non Finnish (NFE) AF: 0.00106 AC: 171 AN: 160988

Other (OTH) AF: 0.0117 AC: 175 AN: 14918

GnomAD4 genome AF: 0.0187 AC: 2829 AN: 151514 Hom.: 69 Cov.: 27 AF XY: 0.0194 AC XY: 1440 AN XY: 74058

African (AFR) AF: 0.0471 AC: 1945 AN: 41316

American (AMR) AF: 0.00630 AC: 96 AN: 15238

Ashkenazi Jewish (ASJ) AF: 0.00144 AC: 5 AN: 3462

East Asian (EAS) AF: 0.0665 AC: 340 AN: 5116

South Asian (SAS) AF: 0.0538 AC: 257 AN: 4778

European-Finnish (FIN) AF: 0.0109 AC: 114 AN: 10486

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

European-Non Finnish (NFE) AF: 0.000664 AC: 45 AN: 67816

Other (OTH) AF: 0.0115 AC: 24 AN: 2096

Alfa AF: 0.000862 Hom.: 2

Bravo AF: 0.0187

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	0.63
DANN	Benign	0.56
PhyloP100		-0.21
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: rs116023034; hg19: chr19-13317908;