rs199793367

Positions:

• chr19-13286647-G-A
• chr19-13286647-G-C

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 3P and 5B. PM2 PP2 BP4 BS2

The NM_001127222.2(CACNA1A):​c.3409C>T​(p.Pro1137Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00000359 in 1,391,286 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 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. P1137A) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 30)
  • Exomes 𝑓: 0.0000036 (0 hom.)
• Consequence: CACNA1A NM_001127222.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.35

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]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), CACNA1A. . Gene score misZ 5.7845 (greater than the threshold 3.09). Trascript score misZ 3.9354 (greater than threshold 3.09). GenCC has associacion of gene with benign paroxysmal torticollis of infancy, developmental and epileptic encephalopathy, 42, undetermined early-onset epileptic encephalopathy, episodic ataxia type 2, familial or sporadic hemiplegic migraine, spinocerebellar ataxia type 6, Lennox-Gastaut syndrome, migraine, familial hemiplegic, 1.
• BP4: Computational evidence support a benign effect (MetaRNN=0.27762195).
• BS2: High AC in GnomAdExome4 at 5 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CACNA1A	NM_001127222.2	c.3409C>T	p.Pro1137Ser	missense_variant	20/47	ENST00000360228.11	NP_001120694.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CACNA1A	ENST00000360228.11	c.3409C>T	p.Pro1137Ser	missense_variant	20/47	1	NM_001127222.2	ENSP00000353362.5
CACNA1A	ENST00000638029.1	c.3421C>T	p.Pro1141Ser	missense_variant	20/48	5		ENSP00000489829.1
CACNA1A	ENST00000573710.7	c.3415C>T	p.Pro1139Ser	missense_variant	20/47	5		ENSP00000460092.3
CACNA1A	ENST00000635727.1	c.3412C>T	p.Pro1138Ser	missense_variant	20/47	5		ENSP00000490001.1
CACNA1A	ENST00000637769.1	c.3412C>T	p.Pro1138Ser	missense_variant	20/47	1		ENSP00000489778.1
CACNA1A	ENST00000636012.1	c.3412C>T	p.Pro1138Ser	missense_variant	20/46	5		ENSP00000490223.1
CACNA1A	ENST00000637736.1	c.3271C>T	p.Pro1091Ser	missense_variant	19/46	5		ENSP00000489861.1
CACNA1A	ENST00000636389.1	c.3412C>T	p.Pro1138Ser	missense_variant	20/47	5		ENSP00000489992.1
CACNA1A	ENST00000637432.1	c.3421C>T	p.Pro1141Ser	missense_variant	20/48	5		ENSP00000490617.1
CACNA1A	ENST00000636549.1	c.3412C>T	p.Pro1138Ser	missense_variant	20/48	5		ENSP00000490578.1
CACNA1A	ENST00000637927.1	c.3415C>T	p.Pro1139Ser	missense_variant	20/47	5		ENSP00000489715.1
CACNA1A	ENST00000635895.1	c.3412C>T	p.Pro1138Ser	missense_variant	20/47	5		ENSP00000490323.1
CACNA1A	ENST00000638009.2	c.3412C>T	p.Pro1138Ser	missense_variant	20/47	1		ENSP00000489913.1
CACNA1A	ENST00000637276.1	c.3412C>T	p.Pro1138Ser	missense_variant	20/46	5		ENSP00000489777.1

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD3 exomes AF: 0.0000156 AC: 3 AN: 191990 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 102226

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000335

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000359 AC: 5 AN: 1391286 Hom.: 0 Cov.: 35 AF XY: 0.00000146 AC XY: 1 AN XY: 684572

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000464

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 30

Alfa AF: 0.0000391 Hom.: 0

ExAC AF: 0.00000834 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.084
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Uncertain	-0.040
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.28	.;T;T;.;.;.;.;.;.;T;.;.;.;T;.
Eigen	Benign	-0.19
Eigen_PC	Benign	0.0015
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Uncertain	0.90	D;D;D;D;D;D;D;D;.;D;D;D;D;D;D
M_CAP	Pathogenic	0.33	D
MetaRNN	Benign	0.28	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Uncertain	0.33	D
MutationAssessor	Benign	0.84	.;.;.;.;L;.;.;.;.;.;.;.;L;.;.
PrimateAI	Uncertain	0.50	T
PROVEAN	Uncertain	-3.0	.;D;.;.;.;.;.;.;.;.;.;.;.;.;.
REVEL	Uncertain	0.32
Sift	Uncertain	0.012	.;D;.;.;.;.;.;.;.;.;.;.;.;.;.
Sift4G	Benign	0.30	T;T;.;.;.;.;.;.;.;.;.;.;.;.;.
Vest4		0.38
MutPred		0.21		.;.;Loss of catalytic residue at P1137 (P = 0.0103);Loss of catalytic residue at P1137 (P = 0.0103);Loss of catalytic residue at P1137 (P = 0.0103);.;Loss of catalytic residue at P1137 (P = 0.0103);.;.;Loss of catalytic residue at P1137 (P = 0.0103);Loss of catalytic residue at P1137 (P = 0.0103);.;Loss of catalytic residue at P1137 (P = 0.0103);.;Loss of catalytic residue at P1137 (P = 0.0103);
MVP		0.84
MPC		0.085
ClinPred		0.90	D
GERP RS		5.1
Varity_R		0.16
gMVP		0.51

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs199793367; hg19: chr19-13397461;