19-13208952-C-G

Variant names:

• chr19-13208952-C-G
• rs373192655
• NM_001127222.2:c.6584G>C

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001127222.2(CACNA1A):​c.6584G>C​(p.Arg2195Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000722 in 1,385,344 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R2195Q) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.2e-7 (0 hom.)
• Consequence: CACNA1A NM_001127222.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.92
• 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: 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: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1A	NM_001127222.2	c.6584G>C	p.Arg2195Pro	missense_variant	Exon 46 of 47	ENST00000360228.11	NP_001120694.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CACNA1A	ENST00000360228.11	c.6584G>C	p.Arg2195Pro	missense_variant	Exon 46 of 47	1	NM_001127222.2	ENSP00000353362.5
CACNA1A	ENST00000638029.1	c.6602G>C	p.Arg2201Pro	missense_variant	Exon 47 of 48	5		ENSP00000489829.1
CACNA1A	ENST00000573710.7	c.6590G>C	p.Arg2197Pro	missense_variant	Exon 46 of 47	5		ENSP00000460092.3
CACNA1A	ENST00000635727.1	c.6587G>C	p.Arg2196Pro	missense_variant	Exon 46 of 47	5		ENSP00000490001.1
CACNA1A	ENST00000637769.1	c.6587G>C	p.Arg2196Pro	missense_variant	Exon 46 of 47	1		ENSP00000489778.1
CACNA1A	ENST00000636012.1	c.6551G>C	p.Arg2184Pro	missense_variant	Exon 45 of 46	5		ENSP00000490223.1
CACNA1A	ENST00000637736.1	c.6446G>C	p.Arg2149Pro	missense_variant	Exon 45 of 46	5		ENSP00000489861.1
CACNA1A	ENST00000636389.1	c.6587G>C	p.Arg2196Pro	missense_variant	Exon 46 of 47	5		ENSP00000489992.1
CACNA1A	ENST00000637432.1	c.6602G>C	p.Arg2201Pro	missense_variant	Exon 47 of 48	5		ENSP00000490617.1
CACNA1A	ENST00000636549.1	c.6593G>C	p.Arg2198Pro	missense_variant	Exon 47 of 48	5		ENSP00000490578.1
CACNA1A	ENST00000637927.1	c.6590G>C	p.Arg2197Pro	missense_variant	Exon 46 of 47	5		ENSP00000489715.1
CACNA1A	ENST00000635895.1	c.6587G>C	p.Arg2196Pro	missense_variant	Exon 46 of 47	5		ENSP00000490323.1
CACNA1A	ENST00000638009.2	c.6587G>C	p.Arg2196Pro	missense_variant	Exon 46 of 47	1		ENSP00000489913.1
CACNA1A	ENST00000637276.1	c.6551G>C	p.Arg2184Pro	missense_variant	Exon 45 of 46	5		ENSP00000489777.1
CACNA1A	ENST00000636768.2	n.*850G>C		non_coding_transcript_exon_variant	Exon 44 of 45	5		ENSP00000490190.2
CACNA1A	ENST00000713789.1	n.*1763G>C		non_coding_transcript_exon_variant	Exon 46 of 47			ENSP00000519091.1
CACNA1A	ENST00000636768.2	n.*850G>C		3_prime_UTR_variant	Exon 44 of 45	5		ENSP00000490190.2
CACNA1A	ENST00000713789.1	n.*1763G>C		3_prime_UTR_variant	Exon 46 of 47			ENSP00000519091.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.22e-7 AC: 1 AN: 1385344 Hom.: 0 Cov.: 37 AF XY: 0.00000146 AC XY: 1 AN XY: 683736

African (AFR) AF: 0.00 AC: 0 AN: 31594

American (AMR) AF: 0.00 AC: 0 AN: 35700

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25178

East Asian (EAS) AF: 0.00 AC: 0 AN: 35706

South Asian (SAS) AF: 0.00 AC: 0 AN: 79228

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 35444

Middle Eastern (MID) AF: 0.000176 AC: 1 AN: 5686

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1078892

Other (OTH) AF: 0.00 AC: 0 AN: 57916

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.61
BayesDel_addAF	Pathogenic	0.23	D
BayesDel_noAF	Uncertain	0.090
CADD	Benign	22
DANN	Uncertain	0.98
DEOGEN2	Benign	0.17	.;.;T;.;.;.;.;.;T;.;.;T;.;.;.;T;.;.
Eigen	Benign	0.019
Eigen_PC	Benign	-0.060
FATHMM_MKL	Benign	0.38	N
LIST_S2	Uncertain	0.88	D;D;D;D;D;D;D;D;D;D;.;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.81	D
MetaRNN	Uncertain	0.63	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	0.99	D
MutationAssessor	Pathogenic	2.9	.;.;.;.;M;.;.;.;.;.;.;.;.;.;.;.;.;.
PhyloP100		1.9
PrimateAI	Uncertain	0.79	T
PROVEAN	Pathogenic	-4.5	.;D;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.
REVEL	Uncertain	0.60
Sift	Uncertain	0.0050	.;D;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.
Sift4G	Uncertain	0.032	D;D;.;.;.;D;.;.;.;.;.;.;.;.;.;.;.;.
Vest4		0.44
MutPred		0.23		.;.;Loss of MoRF binding (P = 0.0088);Loss of MoRF binding (P = 0.0088);Loss of MoRF binding (P = 0.0088);.;.;Loss of MoRF binding (P = 0.0088);.;.;.;.;Loss of MoRF binding (P = 0.0088);.;.;.;.;.;
MVP		0.93
MPC		0.39
ClinPred		0.94	D
GERP RS		3.7
Varity_R		0.70
gMVP		0.27
Mutation Taster		=41/59	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs373192655; hg19: chr19-13319766;