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: 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

ACMG classification

Our verdict: Likely_pathogenic. The variant received 9 ACMG points.

• PM1: In a hotspot region, there are 10 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 7 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 VariationId 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 VariationId is 8497.Status of the report is no_assertion_criteria_provided, 0 stars.

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.2142C>A	p.Asp714Glu	missense	Exon 17 of 47	NP_001120694.1	O00555-8
	CACNA1A	NM_001127221.2	MANE Plus Clinical	c.2145C>A	p.Asp715Glu	missense	Exon 17 of 47	NP_001120693.1	O00555-3
	CACNA1A	NM_023035.3		c.2145C>A	p.Asp715Glu	missense	Exon 17 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.2142C>A	p.Asp714Glu	missense	Exon 17 of 47	ENSP00000353362.5	O00555-8
	CACNA1A	ENST00000638009.2	TSL:1 MANE Plus Clinical	c.2145C>A	p.Asp715Glu	missense	Exon 17 of 47	ENSP00000489913.1	O00555-3
	CACNA1A	ENST00000638029.1	TSL:5	c.2145C>A	p.Asp715Glu	missense	Exon 17 of 48	ENSP00000489829.1	A0A087WW63

Frequencies

GnomAD3 genomes Cov.: 29

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 29

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
1	-	-	Migraine, familial hemiplegic, 1 (1)

Computational scores

Source: dbNSFP v4.9

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
Eigen	Uncertain	0.27
Eigen_PC	Benign	0.21
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Uncertain	0.93	D
M_CAP	Pathogenic	0.61	D
MetaRNN	Pathogenic	0.85	D
MetaSVM	Pathogenic	0.97	D
MutationAssessor	Uncertain	2.5	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
Vest4		0.86
MutPred		0.43		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;