19-13208830-C-T

Position:

• chr19-13208830-C-T

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 1P and 8B. PP2 BP4_Moderate BP6_Moderate BS2

The NM_001127222.2(CACNA1A):​c.6706G>A​(p.Gly2236Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000114 in 1,488,530 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0000067 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000012 (0 hom.)
• Consequence: CACNA1A NM_001127222.2 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.908

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 Benign. Variant got -7 ACMG points.

• 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=0.19969803).
• BP6: Variant 19-13208830-C-T is Benign according to our data. Variant chr19-13208830-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 1493504.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High AC in GnomAdExome4 at 16 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CACNA1A	NM_001127222.2	c.6706G>A	p.Gly2236Ser	missense_variant	46/47	ENST00000360228.11	NP_001120694.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CACNA1A	ENST00000360228.11	c.6706G>A	p.Gly2236Ser	missense_variant	46/47	1	NM_001127222.2	ENSP00000353362.5
CACNA1A	ENST00000638029.1	c.6724G>A	p.Gly2242Ser	missense_variant	47/48	5		ENSP00000489829.1
CACNA1A	ENST00000573710.7	c.6712G>A	p.Gly2238Ser	missense_variant	46/47	5		ENSP00000460092.3
CACNA1A	ENST00000635727.1	c.6709G>A	p.Gly2237Ser	missense_variant	46/47	5		ENSP00000490001.1
CACNA1A	ENST00000637769.1	c.6709G>A	p.Gly2237Ser	missense_variant	46/47	1		ENSP00000489778.1
CACNA1A	ENST00000636012.1	c.6673G>A	p.Gly2225Ser	missense_variant	45/46	5		ENSP00000490223.1
CACNA1A	ENST00000637736.1	c.6568G>A	p.Gly2190Ser	missense_variant	45/46	5		ENSP00000489861.1
CACNA1A	ENST00000636389.1	c.6709G>A	p.Gly2237Ser	missense_variant	46/47	5		ENSP00000489992.1
CACNA1A	ENST00000637432.1	c.6724G>A	p.Gly2242Ser	missense_variant	47/48	5		ENSP00000490617.1
CACNA1A	ENST00000636549.1	c.6715G>A	p.Gly2239Ser	missense_variant	47/48	5		ENSP00000490578.1
CACNA1A	ENST00000637927.1	c.6712G>A	p.Gly2238Ser	missense_variant	46/47	5		ENSP00000489715.1
CACNA1A	ENST00000635895.1	c.6709G>A	p.Gly2237Ser	missense_variant	46/47	5		ENSP00000490323.1
CACNA1A	ENST00000638009.2	c.6709G>A	p.Gly2237Ser	missense_variant	46/47	1		ENSP00000489913.1
CACNA1A	ENST00000637276.1	c.6673G>A	p.Gly2225Ser	missense_variant	45/46	5		ENSP00000489777.1

Frequencies

GnomAD3 genomes AF: 0.00000672 AC: 1 AN: 148816 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000149

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000209 AC: 3 AN: 143846 Hom.: 0 AF XY: 0.0000126 AC XY: 1 AN XY: 79066

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000400

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000856

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000119 AC: 16 AN: 1339714 Hom.: 0 Cov.: 36 AF XY: 0.0000121 AC XY: 8 AN XY: 661154

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000287

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000878

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000665

Gnomad4 OTH exome AF: 0.0000183

GnomAD4 genome AF: 0.00000672 AC: 1 AN: 148816 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 72612

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000149

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000378

ExAC AF: 0.00000925 AC: 1

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Episodic ataxia type 2;C4310716:Developmental and epileptic encephalopathy, 42 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Nov 01, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.067
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.23
CADD	Benign	8.1
DANN	Benign	0.95
DEOGEN2	Benign	0.0098	.;.;T;.;.;.;.;.;T;.;.;T;.;.;.;T;.;.
Eigen	Benign	-0.91
Eigen_PC	Benign	-0.86
FATHMM_MKL	Benign	0.13	N
LIST_S2	Benign	0.81	T;T;T;T;T;T;T;T;T;T;.;T;T;T;T;T;T;T
M_CAP	Pathogenic	0.71	D
MetaRNN	Benign	0.20	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.35	T
MutationAssessor	Benign	0.54	.;.;.;.;N;.;.;.;.;.;.;.;.;.;.;.;.;.
PrimateAI	Uncertain	0.78	T
PROVEAN	Benign	-1.1	.;N;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.
REVEL	Benign	0.21
Sift	Benign	0.69	.;T;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.
Sift4G	Benign	0.82	T;T;.;.;.;T;.;.;.;.;.;.;.;.;.;.;.;.
Vest4		0.052
MutPred		0.27		.;.;Gain of phosphorylation at G2237 (P = 0.0026);Gain of phosphorylation at G2237 (P = 0.0026);Gain of phosphorylation at G2237 (P = 0.0026);.;.;Gain of phosphorylation at G2237 (P = 0.0026);.;.;.;.;Gain of phosphorylation at G2237 (P = 0.0026);.;.;.;.;.;
MVP		0.77
MPC		0.89
ClinPred		0.15	T
GERP RS		0.045
Varity_R		0.070
gMVP		0.10

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

Publications

LitVar

Other links and lift over

dbSNP: rs752808137; hg19: chr19-13319644;