chr19-13286646-G-C

Position:

• chr19-13286646-G-C

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.3410C>G​(p.Pro1137Arg) variant causes a missense change. The variant allele was found at a frequency of 0.000126 in 1,544,684 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). 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: 𝑓 0.00011 (0 hom., cov: 30)
  • Exomes 𝑓: 0.00013 (0 hom.)
• Consequence: CACNA1A NM_001127222.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:4
• 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 -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=0.12688565).
• BP6: Variant 19-13286646-G-C is Benign according to our data. Variant chr19-13286646-G-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 430288.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Uncertain_significance=4}.
• BS2: High AC in GnomAd4 at 16 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CACNA1A	NM_001127222.2	c.3410C>G	p.Pro1137Arg	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.3410C>G	p.Pro1137Arg	missense_variant	20/47	1	NM_001127222.2	ENSP00000353362.5
CACNA1A	ENST00000638029.1	c.3422C>G	p.Pro1141Arg	missense_variant	20/48	5		ENSP00000489829.1
CACNA1A	ENST00000573710.7	c.3416C>G	p.Pro1139Arg	missense_variant	20/47	5		ENSP00000460092.3
CACNA1A	ENST00000635727.1	c.3413C>G	p.Pro1138Arg	missense_variant	20/47	5		ENSP00000490001.1
CACNA1A	ENST00000637769.1	c.3413C>G	p.Pro1138Arg	missense_variant	20/47	1		ENSP00000489778.1
CACNA1A	ENST00000636012.1	c.3413C>G	p.Pro1138Arg	missense_variant	20/46	5		ENSP00000490223.1
CACNA1A	ENST00000637736.1	c.3272C>G	p.Pro1091Arg	missense_variant	19/46	5		ENSP00000489861.1
CACNA1A	ENST00000636389.1	c.3413C>G	p.Pro1138Arg	missense_variant	20/47	5		ENSP00000489992.1
CACNA1A	ENST00000637432.1	c.3422C>G	p.Pro1141Arg	missense_variant	20/48	5		ENSP00000490617.1
CACNA1A	ENST00000636549.1	c.3413C>G	p.Pro1138Arg	missense_variant	20/48	5		ENSP00000490578.1
CACNA1A	ENST00000637927.1	c.3416C>G	p.Pro1139Arg	missense_variant	20/47	5		ENSP00000489715.1
CACNA1A	ENST00000635895.1	c.3413C>G	p.Pro1138Arg	missense_variant	20/47	5		ENSP00000490323.1
CACNA1A	ENST00000638009.2	c.3413C>G	p.Pro1138Arg	missense_variant	20/47	1		ENSP00000489913.1
CACNA1A	ENST00000637276.1	c.3413C>G	p.Pro1138Arg	missense_variant	20/46	5		ENSP00000489777.1

Frequencies

GnomAD3 genomes AF: 0.000105 AC: 16 AN: 151924 Hom.: 0 Cov.: 30

Gnomad AFR AF: 0.0000242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000209

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000177

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000110 AC: 21 AN: 191438 Hom.: 0 AF XY: 0.000108 AC XY: 11 AN XY: 101924

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000769

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000124

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000179

Gnomad OTH exome AF: 0.000226

GnomAD4 exome AF: 0.000128 AC: 178 AN: 1392642 Hom.: 0 Cov.: 35 AF XY: 0.000124 AC XY: 85 AN XY: 685316

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000141

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000153

Gnomad4 SAS exome AF: 0.0000796

Gnomad4 FIN exome AF: 0.0000201

Gnomad4 NFE exome AF: 0.000146

Gnomad4 OTH exome AF: 0.0000349

GnomAD4 genome AF: 0.000105 AC: 16 AN: 152042 Hom.: 0 Cov.: 30 AF XY: 0.0000807 AC XY: 6 AN XY: 74336

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000209

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000177

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000793

ExAC AF: 0.000108 AC: 13

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3 Benign:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:2 Benign:1

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 13, 2020	In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Has not been previously published as pathogenic or benign to our knowledge -
Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jan 14, 2020	- -
Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	May 01, 2022	CACNA1A: PP2 -

Spinocerebellar ataxia type 6;C1720416:Episodic ataxia type 2;C1832884:Migraine, familial hemiplegic, 1;C4310716:Developmental and epileptic encephalopathy, 42 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 31, 2018

- -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Athena Diagnostics

Jan 24, 2024

- -

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

Oct 08, 2023

- -

Inborn genetic diseases Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 28, 2023

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.041	T
BayesDel_noAF	Uncertain	-0.020
CADD	Uncertain	24
DANN	Benign	0.93
DEOGEN2	Uncertain	0.45	.;T;T;.;.;.;.;.;.;T;.;.;.;T;.
Eigen	Benign	-0.21
Eigen_PC	Benign	-0.0043
FATHMM_MKL	Benign	0.70	D
LIST_S2	Uncertain	0.88	D;D;D;D;D;D;D;D;.;D;D;D;D;D;D
M_CAP	Pathogenic	0.35	D
MetaRNN	Benign	0.13	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Uncertain	0.29	D
MutationAssessor	Benign	1.7	.;.;.;.;L;.;.;.;.;.;.;.;L;.;.
PrimateAI	Uncertain	0.57	T
PROVEAN	Uncertain	-3.4	.;D;.;.;.;.;.;.;.;.;.;.;.;.;.
REVEL	Uncertain	0.32
Sift	Uncertain	0.0040	.;D;.;.;.;.;.;.;.;.;.;.;.;.;.
Sift4G	Benign	0.13	T;T;.;.;.;.;.;.;.;.;.;.;.;.;.
Vest4		0.47
MutPred		0.24		.;.;Loss of glycosylation at P1138 (P = 0.0032);Loss of glycosylation at P1138 (P = 0.0032);Loss of glycosylation at P1138 (P = 0.0032);.;Loss of glycosylation at P1138 (P = 0.0032);.;.;Loss of glycosylation at P1138 (P = 0.0032);Loss of glycosylation at P1138 (P = 0.0032);.;Loss of glycosylation at P1138 (P = 0.0032);.;Loss of glycosylation at P1138 (P = 0.0032);
MVP		0.78
MPC		0.093
ClinPred		0.27	T
GERP RS		5.1
Varity_R		0.25
gMVP		0.56

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: rs200333359; hg19: chr19-13397460;