19-13212668-C-T

Position:

• chr19-13212668-C-T

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 1P and 7B. PP2 BP4_Moderate BP6 BS2

The NM_001127222.2(CACNA1A):​c.6013G>A​(p.Ala2005Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000218 in 1,512,660 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.000046 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000019 (0 hom.)
• Consequence: CACNA1A NM_001127222.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:3
• Conservation: PhyloP100: 3.06

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 (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -6 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=0.08892241).
• BP6: Variant 19-13212668-C-T is Benign according to our data. Variant chr19-13212668-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 446936.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}. Variant chr19-13212668-C-T is described in Lovd as [Likely_benign].
• BS2: High AC in GnomAd4 at 7 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CACNA1A	NM_001127222.2	c.6013G>A	p.Ala2005Thr	missense_variant	41/47	ENST00000360228.11	NP_001120694.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CACNA1A	ENST00000360228.11	c.6013G>A	p.Ala2005Thr	missense_variant	41/47	1	NM_001127222.2	ENSP00000353362.5
CACNA1A	ENST00000638029.1	c.6031G>A	p.Ala2011Thr	missense_variant	42/48	5		ENSP00000489829.1
CACNA1A	ENST00000573710.7	c.6019G>A	p.Ala2007Thr	missense_variant	41/47	5		ENSP00000460092.3
CACNA1A	ENST00000635727.1	c.6016G>A	p.Ala2006Thr	missense_variant	41/47	5		ENSP00000490001.1
CACNA1A	ENST00000637769.1	c.6016G>A	p.Ala2006Thr	missense_variant	41/47	1		ENSP00000489778.1
CACNA1A	ENST00000636012.1	c.6016G>A	p.Ala2006Thr	missense_variant	41/46	5		ENSP00000490223.1
CACNA1A	ENST00000637736.1	c.5875G>A	p.Ala1959Thr	missense_variant	40/46	5		ENSP00000489861.1
CACNA1A	ENST00000636389.1	c.6016G>A	p.Ala2006Thr	missense_variant	41/47	5		ENSP00000489992.1
CACNA1A	ENST00000637432.1	c.6031G>A	p.Ala2011Thr	missense_variant	42/48	5		ENSP00000490617.1
CACNA1A	ENST00000636549.1	c.6022G>A	p.Ala2008Thr	missense_variant	42/48	5		ENSP00000490578.1
CACNA1A	ENST00000637927.1	c.6019G>A	p.Ala2007Thr	missense_variant	41/47	5		ENSP00000489715.1
CACNA1A	ENST00000635895.1	c.6016G>A	p.Ala2006Thr	missense_variant	41/47	5		ENSP00000490323.1
CACNA1A	ENST00000638009.2	c.6016G>A	p.Ala2006Thr	missense_variant	41/47	1		ENSP00000489913.1
CACNA1A	ENST00000637276.1	c.6016G>A	p.Ala2006Thr	missense_variant	41/46	5		ENSP00000489777.1
CACNA1A	ENST00000636768.1	n.*315G>A		non_coding_transcript_exon_variant	6/10	5		ENSP00000490190.2
CACNA1A	ENST00000636768.1	n.*315G>A		3_prime_UTR_variant	6/10	5		ENSP00000490190.2

Frequencies

GnomAD3 genomes AF: 0.0000461 AC: 7 AN: 152006 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000580

Gnomad SAS AF: 0.000415

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000690 AC: 11 AN: 159378 Hom.: 0 AF XY: 0.0000714 AC XY: 6 AN XY: 84006

Gnomad AFR exome AF: 0.0000811

Gnomad AMR exome AF: 0.0000491

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000549

Gnomad SAS exome AF: 0.0000761

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000191 AC: 26 AN: 1360536 Hom.: 0 Cov.: 33 AF XY: 0.0000195 AC XY: 13 AN XY: 665500

Gnomad4 AFR exome AF: 0.0000329

Gnomad4 AMR exome AF: 0.0000336

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000417

Gnomad4 SAS exome AF: 0.0000575

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000188

Gnomad4 OTH exome AF: 0.0000357

GnomAD4 genome AF: 0.0000460 AC: 7 AN: 152124 Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2 AN XY: 74376

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000581

Gnomad4 SAS AF: 0.000415

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000378

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000121 AC: 1

ExAC AF: 0.0000423 AC: 5

Asia WGS AF: 0.00346 AC: 12 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:2

Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Athena Diagnostics

Feb 09, 2017

- -

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

Sep 01, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.071
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Uncertain	-0.080
CADD	Uncertain	24
DANN	Benign	0.79
DEOGEN2	Benign	0.014	.;.;T;.;.;.;.;.;T;.;.;T;.;.;.;T;.;.
Eigen	Benign	-0.31
Eigen_PC	Benign	-0.22
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Uncertain	0.87	D;D;D;D;D;D;D;D;D;D;.;D;D;D;D;D;D;D
M_CAP	Uncertain	0.12	D
MetaRNN	Benign	0.089	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Uncertain	0.15	D
MutationAssessor	Uncertain	2.3	.;.;.;.;M;.;.;.;.;.;.;.;.;.;M;.;.;.
PrimateAI	Uncertain	0.59	T
PROVEAN	Benign	-0.80	.;N;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.
REVEL	Benign	0.26
Sift	Benign	0.33	.;T;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.
Sift4G	Benign	0.47	T;T;.;.;.;T;.;.;.;.;.;.;.;.;.;.;.;.
Vest4		0.28
MVP		0.88
MPC		0.68
ClinPred		0.050	T
GERP RS		2.4
Varity_R		0.055
gMVP		0.22

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: rs374063403; hg19: chr19-13323482;