19-13298766-C-A

Position:

• chr19-13298766-C-A

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.2867G>T​(p.Arg956Leu) variant causes a missense change. The variant allele was found at a frequency of 0.0000697 in 1,520,538 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 0.000085 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000068 (0 hom.)
• Consequence: CACNA1A NM_001127222.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:3
• Conservation: PhyloP100: 4.66

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 -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=0.16620159).
• BP6: Variant 19-13298766-C-A is Benign according to our data. Variant chr19-13298766-C-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 422571.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1, Benign=2}.
• BS2: High AC in GnomAd4 at 13 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CACNA1A	NM_001127222.2	c.2867G>T	p.Arg956Leu	missense_variant	19/47	ENST00000360228.11	NP_001120694.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CACNA1A	ENST00000360228.11	c.2867G>T	p.Arg956Leu	missense_variant	19/47	1	NM_001127222.2	ENSP00000353362.5
CACNA1A	ENST00000638029.1	c.2879G>T	p.Arg960Leu	missense_variant	19/48	5		ENSP00000489829.1
CACNA1A	ENST00000573710.7	c.2873G>T	p.Arg958Leu	missense_variant	19/47	5		ENSP00000460092.3
CACNA1A	ENST00000635727.1	c.2870G>T	p.Arg957Leu	missense_variant	19/47	5		ENSP00000490001.1
CACNA1A	ENST00000637769.1	c.2870G>T	p.Arg957Leu	missense_variant	19/47	1		ENSP00000489778.1
CACNA1A	ENST00000636012.1	c.2870G>T	p.Arg957Leu	missense_variant	19/46	5		ENSP00000490223.1
CACNA1A	ENST00000637736.1	c.2729G>T	p.Arg910Leu	missense_variant	18/46	5		ENSP00000489861.1
CACNA1A	ENST00000636389.1	c.2870G>T	p.Arg957Leu	missense_variant	19/47	5		ENSP00000489992.1
CACNA1A	ENST00000637432.1	c.2879G>T	p.Arg960Leu	missense_variant	19/48	5		ENSP00000490617.1
CACNA1A	ENST00000636549.1	c.2870G>T	p.Arg957Leu	missense_variant	19/48	5		ENSP00000490578.1
CACNA1A	ENST00000637927.1	c.2873G>T	p.Arg958Leu	missense_variant	19/47	5		ENSP00000489715.1
CACNA1A	ENST00000635895.1	c.2870G>T	p.Arg957Leu	missense_variant	19/47	5		ENSP00000490323.1
CACNA1A	ENST00000638009.2	c.2870G>T	p.Arg957Leu	missense_variant	19/47	1		ENSP00000489913.1
CACNA1A	ENST00000637276.1	c.2870G>T	p.Arg957Leu	missense_variant	19/46	5		ENSP00000489777.1

Frequencies

GnomAD3 genomes AF: 0.0000855 AC: 13 AN: 152106 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000192 AC: 23 AN: 120104 Hom.: 0 AF XY: 0.000253 AC XY: 17 AN XY: 67224

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00233

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000247

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000206

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000680 AC: 93 AN: 1368432 Hom.: 0 Cov.: 32 AF XY: 0.0000784 AC XY: 53 AN XY: 675952

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00177

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000169

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000288

Gnomad4 OTH exome AF: 0.0000878

GnomAD4 genome AF: 0.0000855 AC: 13 AN: 152106 Hom.: 0 Cov.: 33 AF XY: 0.0000807 AC XY: 6 AN XY: 74322

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000375 Hom.: 0

Bravo AF: 0.0000529

ExAC AF: 0.0000892 AC: 9

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 05, 2019	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 03, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Mar 12, 2018	- -

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

Jan 25, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.47
BayesDel_addAF	Benign	-0.026	T
BayesDel_noAF	Uncertain	0.020
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.10	.;.;T;.;.;.;.;.;.;T;.;.;.;T;.
Eigen	Benign	0.18
Eigen_PC	Benign	0.14
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.96	D;D;D;D;D;D;D;D;.;D;D;D;D;D;D
M_CAP	Pathogenic	0.87	D
MetaRNN	Benign	0.17	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Uncertain	0.56	D
MutationAssessor	Benign	1.4	.;.;.;.;L;.;.;.;.;.;.;.;L;.;.
PrimateAI	Pathogenic	0.95	D
PROVEAN	Uncertain	-4.2	.;D;.;.;.;.;.;.;.;.;.;.;.;.;.
REVEL	Uncertain	0.53
Sift	Benign	0.083	.;T;.;.;.;.;.;.;.;.;.;.;.;.;.
Sift4G	Uncertain	0.023	D;D;.;.;.;.;.;.;.;.;.;.;.;.;.
Vest4		0.57
MVP		0.89
MPC		2.4
ClinPred		0.24	T
GERP RS		4.2
Varity_R		0.38
gMVP		0.76

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: rs551380805; hg19: chr19-13409580;