rs111240372

Variant names:

• chr19-13207011-T-C
• rs111240372
• ENST00000636768.2:n.*2084A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The ENST00000713789.1(CACNA1A):​n.*3002A>G variant causes a non coding transcript exon change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00746 in 154,954 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0074 (4 hom., cov: 26)
  • Exomes 𝑓: 0.0078 (0 hom.)
• Consequence: CACNA1A ENST00000713789.1 non_coding_transcript_exon
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.38
• 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.49).
• BP6: Variant 19-13207011-T-C is Benign according to our data. Variant chr19-13207011-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 1211720.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00742 (1024/138080) while in subpopulation NFE AF = 0.0102 (662/65060). AF 95% confidence interval is 0.00953. There are 4 homozygotes in GnomAd4. There are 497 alleles in the male GnomAd4 subpopulation. Median coverage is 26. This position passed quality control check.
• BS2: High AC in GnomAd4 at 1024 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1A	NM_001127222.2	c.*302A>G		3_prime_UTR_variant	Exon 47 of 47	ENST00000360228.11	NP_001120694.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CACNA1A	ENST00000636768.2	n.*2084A>G		non_coding_transcript_exon_variant	Exon 45 of 45	5		ENSP00000490190.2
CACNA1A	ENST00000713789.1	n.*3002A>G		non_coding_transcript_exon_variant	Exon 47 of 47			ENSP00000519091.1
CACNA1A	ENST00000360228.11	c.*302A>G		3_prime_UTR_variant	Exon 47 of 47	1	NM_001127222.2	ENSP00000353362.5
CACNA1A	ENST00000637769.1	c.*302A>G		3_prime_UTR_variant	Exon 47 of 47	1		ENSP00000489778.1
CACNA1A	ENST00000637736.1	c.*302A>G		3_prime_UTR_variant	Exon 46 of 46	5		ENSP00000489861.1
CACNA1A	ENST00000636389.1	c.*909A>G		3_prime_UTR_variant	Exon 47 of 47	5		ENSP00000489992.1
CACNA1A	ENST00000635895.1	c.*1035A>G		3_prime_UTR_variant	Exon 47 of 47	5		ENSP00000490323.1
CACNA1A	ENST00000638009.2	c.*1035A>G		3_prime_UTR_variant	Exon 47 of 47	1		ENSP00000489913.1
CACNA1A	ENST00000636768.2	n.*2084A>G		3_prime_UTR_variant	Exon 45 of 45	5		ENSP00000490190.2
CACNA1A	ENST00000713789.1	n.*3002A>G		3_prime_UTR_variant	Exon 47 of 47			ENSP00000519091.1

Frequencies

GnomAD3 genomes AF: 0.00742 AC: 1024 AN: 137992 Hom.: 4 Cov.: 26

Gnomad AFR AF: 0.00133

Gnomad AMI AF: 0.00115

Gnomad AMR AF: 0.00677

Gnomad ASJ AF: 0.00624

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00177

Gnomad FIN AF: 0.0228

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0102

Gnomad OTH AF: 0.00677

GnomAD4 exome AF: 0.00782 AC: 132 AN: 16874 Hom.: 0 Cov.: 0 AF XY: 0.00850 AC XY: 76 AN XY: 8944

African (AFR) AF: 0.00226 AC: 1 AN: 442

American (AMR) AF: 0.00813 AC: 4 AN: 492

Ashkenazi Jewish (ASJ) AF: 0.00469 AC: 3 AN: 640

East Asian (EAS) AF: 0.00 AC: 0 AN: 1770

South Asian (SAS) AF: 0.00163 AC: 1 AN: 614

European-Finnish (FIN) AF: 0.0165 AC: 23 AN: 1396

Middle Eastern (MID) AF: 0.0217 AC: 2 AN: 92

European-Non Finnish (NFE) AF: 0.00844 AC: 87 AN: 10314

Other (OTH) AF: 0.00987 AC: 11 AN: 1114

GnomAD4 genome AF: 0.00742 AC: 1024 AN: 138080 Hom.: 4 Cov.: 26 AF XY: 0.00750 AC XY: 497 AN XY: 66266

African (AFR) AF: 0.00133 AC: 49 AN: 36852

American (AMR) AF: 0.00676 AC: 90 AN: 13320

Ashkenazi Jewish (ASJ) AF: 0.00624 AC: 21 AN: 3366

East Asian (EAS) AF: 0.00 AC: 0 AN: 4490

South Asian (SAS) AF: 0.00177 AC: 7 AN: 3962

European-Finnish (FIN) AF: 0.0228 AC: 181 AN: 7956

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 274

European-Non Finnish (NFE) AF: 0.0102 AC: 662 AN: 65060

Other (OTH) AF: 0.00672 AC: 13 AN: 1934

Alfa AF: 0.00731 Hom.: 0

Bravo AF: 0.00628

Asia WGS AF: 0.00202 AC: 8 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jun 19, 2018

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.49
CADD	Benign	11
DANN	Benign	0.88
PhyloP100		1.4
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: rs111240372; hg19: chr19-13317825;