rs121908244

Variant names:

• chr19-13228722-A-G
• rs121908244
• ENST00000573710.7:c.5608T>C

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM1 PM2 PP3_Moderate

The ENST00000573710.7(CACNA1A):​c.5608T>C​(p.Cys1870Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as not provided (no stars).

• Frequency: Genomes: not found (cov: 30)
• Consequence: CACNA1A ENST00000573710.7 missense
• Clinical Significance: not provided no classification provided O:1
• Conservation: PhyloP100: 9.20
• Publications: 3 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: Likely_pathogenic. The variant received 6 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 12 uncertain in ENST00000573710.7
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.87

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1A	NM_001127222.2	c.5529-1195T>C		intron_variant	Intron 36 of 46	ENST00000360228.11	NP_001120694.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CACNA1A	ENST00000573710.7	c.5608T>C	p.Cys1870Arg	missense_variant	Exon 37 of 47	5		ENSP00000460092.3
CACNA1A	ENST00000637769.1	c.5605T>C	p.Cys1869Arg	missense_variant	Exon 37 of 47	1		ENSP00000489778.1
CACNA1A	ENST00000637736.1	c.5464T>C	p.Cys1822Arg	missense_variant	Exon 36 of 46	5		ENSP00000489861.1
CACNA1A	ENST00000636389.1	c.5605T>C	p.Cys1869Arg	missense_variant	Exon 37 of 47	5		ENSP00000489992.1
CACNA1A	ENST00000637927.1	c.5608T>C	p.Cys1870Arg	missense_variant	Exon 37 of 47	5		ENSP00000489715.1
CACNA1A	ENST00000638009.2	c.5605T>C	p.Cys1869Arg	missense_variant	Exon 37 of 47	1		ENSP00000489913.1
CACNA1A	ENST00000360228.11	c.5529-1195T>C		intron_variant	Intron 36 of 46	1	NM_001127222.2	ENSP00000353362.5
CACNA1A	ENST00000638029.1	c.5547-1195T>C		intron_variant	Intron 37 of 47	5		ENSP00000489829.1
CACNA1A	ENST00000635727.1	c.5532-1195T>C		intron_variant	Intron 36 of 46	5		ENSP00000490001.1
CACNA1A	ENST00000636012.1	c.5532-1195T>C		intron_variant	Intron 36 of 45	5		ENSP00000490223.1
CACNA1A	ENST00000637432.1	c.5547-1195T>C		intron_variant	Intron 37 of 47	5		ENSP00000490617.1
CACNA1A	ENST00000636549.1	c.5538-1195T>C		intron_variant	Intron 37 of 47	5		ENSP00000490578.1
CACNA1A	ENST00000635895.1	c.5532-1195T>C		intron_variant	Intron 36 of 46	5		ENSP00000490323.1
CACNA1A	ENST00000637276.1	c.5532-1195T>C		intron_variant	Intron 36 of 45	5		ENSP00000489777.1
CACNA1A	ENST00000636768.2	n.5531+1360T>C		intron_variant	Intron 36 of 44	5		ENSP00000490190.2
CACNA1A	ENST00000713789.1	n.*709+1360T>C		intron_variant	Intron 37 of 46			ENSP00000519091.1

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome Cov.: 27

GnomAD4 genome Cov.: 30

ClinVar

Significance: not provided

Submissions summary: Other:1

Revision: no classification provided

Submissions by phenotype

Episodic ataxia type 2 Other:1

-

UniProtKB/Swiss-Prot

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.56	D
BayesDel_noAF	Pathogenic	0.56
CADD	Benign	20
DANN	Uncertain	0.99
DEOGEN2	Benign	0.25	T;.;.;.;.;.;T;.
Eigen	Pathogenic	0.81
Eigen_PC	Pathogenic	0.70
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Pathogenic	1.0	D;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.60	D
MetaRNN	Pathogenic	0.87	D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.30	D
PhyloP100		9.2
Sift4G	Pathogenic	0.0	.;.;D;.;.;.;.;.
MutPred		0.60		Gain of disorder (P = 0.0059);Gain of disorder (P = 0.0059);.;.;Gain of disorder (P = 0.0059);.;.;.;
MVP		0.97
ClinPred		0.87	D
GERP RS		4.2
Mutation Taster		=23/77	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs121908244; hg19: chr19-13339536;