chr19-13303877-G-A

Variant names:

• chr19-13303877-G-A
• rs121908212
• NM_001127222.2:c.1994C>T

Variant summary

Our verdict is Pathogenic. The variant received 20 ACMG points: 20P and 0B. PS3 PM1 PM2 PP3_Strong PP5_Very_Strong

The NM_001127222.2(CACNA1A):​c.1994C>T​(p.Thr665Met) 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. 13/22 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV000612511: Assessment of experimental evidence suggests this variant results in abnormal protein function. (PMID:10024348, 22190617, 9488686)" and additional evidence is available in ClinVar. Synonymous variant affecting the same amino acid position (i.e. T665T) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 30)
• Consequence: CACNA1A NM_001127222.2 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:18 O:3
• Conservation: PhyloP100: 9.85
• Publications: 56 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: Pathogenic. The variant received 20 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV000612511: Assessment of experimental evidence suggests this variant results in abnormal protein function. (PMID:10024348, 22190617, 9488686); SCV002512902: Published functional studies demonstrate that the variant leads to loss-of-function for the P/Q-type channel activity, which significantly alters channel inactivation kinetics resulting in defective voltage-dependent gating to support calcium influx (Kraus et al., 1998; Barrett et al., 2005; Tao et al., 2012); PMID: 30180405, 28717674, 10024348, 22136990, 24270521, 25274239, 22190617, 9488686, 22969264, 22000314, 25266619, 24498617, 27290639, 11971066, 11814735, 28169007, 18279427, 15795222, 12056940, 10987655, 8898206, 9915947, 12756131, 28856914, 29915382, 29486580, 31824404, 31692161, 14718690, 11439943, 31935766, 30063100, 31115040, 30027842; SCV000941934: Experimental studies have shown that this missense change affects CACNA1A function (PMID: 9488686, 10024348).; SCV004020795: "At least two publication reports experimental evidence evaluating an impact on protein function (example, Hans_1999). The most pronounced variant effect results in decreased density of functional channels and their unitary conductance consistent with a loss of function mechanism od disease." PMID: 11439943, 25266619, 10024348; SCV005329541: Experimental studies have shown that this missense change affects CACNA1A function (Hans M, et al., 1999).; SCV002717687: "In vitro studies showed defective voltage-dependent gating associated with the p.T666M pathogenic mutation (Barrett, 2005)."; SCV002318456: "Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID: 10024348, 22190617, 9488686)."
• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 11 uncertain in NM_001127222.2
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.976
• PP5: Variant 19-13303877-G-A is Pathogenic according to our data. Variant chr19-13303877-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 8488.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 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.1994C>T	p.Thr665Met	missense	Exon 16 of 47	NP_001120694.1	O00555-8
	CACNA1A	NM_001127221.2	MANE Plus Clinical	c.1997C>T	p.Thr666Met	missense	Exon 16 of 47	NP_001120693.1	O00555-3
	CACNA1A	NM_023035.3		c.1997C>T	p.Thr666Met	missense	Exon 16 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.1994C>T	p.Thr665Met	missense	Exon 16 of 47	ENSP00000353362.5	O00555-8
	CACNA1A	ENST00000638009.2	TSL:1 MANE Plus Clinical	c.1997C>T	p.Thr666Met	missense	Exon 16 of 47	ENSP00000489913.1	O00555-3
	CACNA1A	ENST00000638029.1	TSL:5	c.1997C>T	p.Thr666Met	missense	Exon 16 of 48	ENSP00000489829.1	A0A087WW63

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 30

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
5	-	-	not provided (5)
4	-	-	Migraine, familial hemiplegic, 1 (5)
2	-	-	Developmental and epileptic encephalopathy, 42 (2)
2	-	-	Episodic ataxia type 2 (2)
1	-	-	CACNA1A-related disorder (1)
1	-	-	Episodic ataxia type 2;C4310716:Developmental and epileptic encephalopathy, 42 (1)
1	-	-	Inborn genetic diseases (1)
1	-	-	Migraine, sporadic hemiplegic, with progressive cerebellar ataxia (1)
1	-	-	Spinocerebellar ataxia type 6;C1720416:Episodic ataxia type 2;C1832884:Migraine, familial hemiplegic, 1;C4310716:Developmental and epileptic encephalopathy, 42 (1)
-	-	-	Familial hemiplegic migraine (1)
-	-	-	Spinocerebellar ataxia type 6;C1720416:Episodic ataxia type 2;C1832884:Migraine, familial hemiplegic, 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.58	D
BayesDel_noAF	Pathogenic	0.59
CADD	Pathogenic	33
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.50	D
Eigen	Pathogenic	0.74
Eigen_PC	Uncertain	0.61
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Pathogenic	0.82	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.3	H
PhyloP100		9.9
PrimateAI	Pathogenic	0.80	T
PROVEAN	Pathogenic	-5.5	D
REVEL	Pathogenic	0.96
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Vest4		0.96
MutPred		0.86		Gain of catalytic residue at T666 (P = 0.0778)
MVP		0.99
MPC		2.3
ClinPred		1.0	D
GERP RS		3.5
Varity_R		0.77
gMVP		0.99
Mutation Taster		=8/92	disease causing (ClinVar)

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: rs121908212; hg19: chr19-13414691; COSMIC: COSV64189612; COSMIC: COSV64189612;