19-13303576-G-T

Variant names:

• chr19-13303576-G-T
• rs121908218
• NM_001127222.2:c.2142C>A

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 9P and 0B. PM1 PM2 PM5 PP3_Moderate PP5

The NM_001127222.2(CACNA1A):​c.2142C>A​(p.Asp714Glu) variant causes a missense change involving the alteration of a non-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 Pathogenic (no stars). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D714H) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 29)
• Consequence: CACNA1A NM_001127222.2 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 0.786
• Publications: 9 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 9 ACMG points.

• PM1: In a hotspot region, there are 7 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 6 uncertain in NM_001127222.2
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr19-13303578-C-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 2949239.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.853
• PP5: Variant 19-13303576-G-T is Pathogenic according to our data. Variant chr19-13303576-G-T is described in ClinVar as [Pathogenic]. Clinvar id is 8497.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1A	NM_001127222.2	c.2142C>A	p.Asp714Glu	missense_variant	Exon 17 of 47	ENST00000360228.11	NP_001120694.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CACNA1A	ENST00000360228.11	c.2142C>A	p.Asp714Glu	missense_variant	Exon 17 of 47	1	NM_001127222.2	ENSP00000353362.5
CACNA1A	ENST00000638029.1	c.2145C>A	p.Asp715Glu	missense_variant	Exon 17 of 48	5		ENSP00000489829.1
CACNA1A	ENST00000573710.7	c.2148C>A	p.Asp716Glu	missense_variant	Exon 17 of 47	5		ENSP00000460092.3
CACNA1A	ENST00000635727.1	c.2145C>A	p.Asp715Glu	missense_variant	Exon 17 of 47	5		ENSP00000490001.1
CACNA1A	ENST00000637769.1	c.2145C>A	p.Asp715Glu	missense_variant	Exon 17 of 47	1		ENSP00000489778.1
CACNA1A	ENST00000636012.1	c.2145C>A	p.Asp715Glu	missense_variant	Exon 17 of 46	5		ENSP00000490223.1
CACNA1A	ENST00000637736.1	c.2004C>A	p.Asp668Glu	missense_variant	Exon 16 of 46	5		ENSP00000489861.1
CACNA1A	ENST00000636389.1	c.2145C>A	p.Asp715Glu	missense_variant	Exon 17 of 47	5		ENSP00000489992.1
CACNA1A	ENST00000637432.1	c.2145C>A	p.Asp715Glu	missense_variant	Exon 17 of 48	5		ENSP00000490617.1
CACNA1A	ENST00000636549.1	c.2145C>A	p.Asp715Glu	missense_variant	Exon 17 of 48	5		ENSP00000490578.1
CACNA1A	ENST00000637927.1	c.2148C>A	p.Asp716Glu	missense_variant	Exon 17 of 47	5		ENSP00000489715.1
CACNA1A	ENST00000635895.1	c.2145C>A	p.Asp715Glu	missense_variant	Exon 17 of 47	5		ENSP00000490323.1
CACNA1A	ENST00000638009.2	c.2145C>A	p.Asp715Glu	missense_variant	Exon 17 of 47	1		ENSP00000489913.1
CACNA1A	ENST00000637276.1	c.2145C>A	p.Asp715Glu	missense_variant	Exon 17 of 46	5		ENSP00000489777.1
CACNA1A	ENST00000636768.2	n.2145C>A		non_coding_transcript_exon_variant	Exon 17 of 45	5		ENSP00000490190.2
CACNA1A	ENST00000713789.1	n.2142C>A		non_coding_transcript_exon_variant	Exon 17 of 47			ENSP00000519091.1

Frequencies

GnomAD3 genomes Cov.: 29

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 29

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Migraine, familial hemiplegic, 1 Pathogenic:1

Sep 20, 2016

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.43	D
BayesDel_noAF	Pathogenic	0.38
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Benign	0.23	.;.;T;.;.;.;.;.;.;T;.;.;.;T;.
Eigen	Uncertain	0.27
Eigen_PC	Benign	0.21
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Uncertain	0.93	D;D;D;D;D;D;D;D;.;D;D;D;D;D;D
M_CAP	Pathogenic	0.61	D
MetaRNN	Pathogenic	0.85	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	0.97	D
MutationAssessor	Uncertain	2.5	.;.;.;.;M;.;.;M;.;.;.;.;M;.;.
PhyloP100		0.79
PrimateAI	Pathogenic	0.92	D
PROVEAN	Uncertain	-3.7	.;D;.;.;.;.;.;.;.;.;.;.;.;.;.
REVEL	Pathogenic	0.77
Sift	Pathogenic	0.0	.;D;.;.;.;.;.;.;.;.;.;.;.;.;.
Sift4G	Uncertain	0.0020	D;D;.;.;.;.;.;.;.;.;.;.;.;.;.
Vest4		0.86
MutPred		0.43		Gain of disorder (P = 0.1529);.;Gain of disorder (P = 0.1529);Gain of disorder (P = 0.1529);Gain of disorder (P = 0.1529);.;Gain of disorder (P = 0.1529);Gain of disorder (P = 0.1529);Gain of disorder (P = 0.1529);Gain of disorder (P = 0.1529);Gain of disorder (P = 0.1529);.;Gain of disorder (P = 0.1529);.;Gain of disorder (P = 0.1529);
MVP		0.97
MPC		2.2
ClinPred		0.99	D
GERP RS		1.4
Varity_R		0.73
gMVP		0.97
Mutation Taster		=3/97	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.090		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: rs121908218; hg19: chr19-13414390;