rs121908242

Variant names:

• chr19-13298946-G-A
• rs121908242
• NM_001127222.2:c.2687C>T

Your query was ambiguous. Multiple possible variants found:

• chr19-13298946-G-A
• chr19-13298946-G-C

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Moderate BP6_Very_Strong BS2

The NM_001127222.2(CACNA1A):​c.2687C>T​(p.Pro896Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000903 in 1,439,062 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P896R) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000090 (0 hom.)
• Consequence: CACNA1A NM_001127222.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 2.73
• Publications: 6 publications found

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 Gene-Disease associations (from GenCC):

• episodic ataxia type 2

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Ambry Genetics, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
• undetermined early-onset epileptic encephalopathy

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, Illumina
• developmental and epileptic encephalopathy, 42

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• migraine, familial hemiplegic, 1

  Inheritance: AD Classification: STRONG Submitted by: Ambry Genetics, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
• spinocerebellar ataxia type 6

  Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Ambry Genetics, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Orphanet
• benign paroxysmal torticollis of infancy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• familial or sporadic hemiplegic migraine

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Lennox-Gastaut syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.19471204).
• BP6: Variant 19-13298946-G-A is Benign according to our data. Variant chr19-13298946-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 943049.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAdExome4 at 13 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1A	NM_001127222.2	c.2687C>T	p.Pro896Leu	missense_variant	Exon 19 of 47	ENST00000360228.11	NP_001120694.1
CACNA1A	NM_001127221.2	c.2690C>T	p.Pro897Leu	missense_variant	Exon 19 of 47	ENST00000638009.2	NP_001120693.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CACNA1A	ENST00000360228.11	c.2687C>T	p.Pro896Leu	missense_variant	Exon 19 of 47	1	NM_001127222.2	ENSP00000353362.5
CACNA1A	ENST00000638009.2	c.2690C>T	p.Pro897Leu	missense_variant	Exon 19 of 47	1	NM_001127221.2	ENSP00000489913.1
CACNA1A	ENST00000638029.1	c.2699C>T	p.Pro900Leu	missense_variant	Exon 19 of 48	5		ENSP00000489829.1
CACNA1A	ENST00000573710.7	c.2693C>T	p.Pro898Leu	missense_variant	Exon 19 of 47	5		ENSP00000460092.3
CACNA1A	ENST00000635727.1	c.2690C>T	p.Pro897Leu	missense_variant	Exon 19 of 47	5		ENSP00000490001.1
CACNA1A	ENST00000637769.1	c.2690C>T	p.Pro897Leu	missense_variant	Exon 19 of 47	1		ENSP00000489778.1
CACNA1A	ENST00000636012.1	c.2690C>T	p.Pro897Leu	missense_variant	Exon 19 of 46	5		ENSP00000490223.1
CACNA1A	ENST00000637736.1	c.2549C>T	p.Pro850Leu	missense_variant	Exon 18 of 46	5		ENSP00000489861.1
CACNA1A	ENST00000636389.1	c.2690C>T	p.Pro897Leu	missense_variant	Exon 19 of 47	5		ENSP00000489992.1
CACNA1A	ENST00000637432.1	c.2699C>T	p.Pro900Leu	missense_variant	Exon 19 of 48	5		ENSP00000490617.1
CACNA1A	ENST00000636549.1	c.2690C>T	p.Pro897Leu	missense_variant	Exon 19 of 48	5		ENSP00000490578.1
CACNA1A	ENST00000637927.1	c.2693C>T	p.Pro898Leu	missense_variant	Exon 19 of 47	5		ENSP00000489715.1
CACNA1A	ENST00000635895.1	c.2690C>T	p.Pro897Leu	missense_variant	Exon 19 of 47	5		ENSP00000490323.1
CACNA1A	ENST00000637276.1	c.2690C>T	p.Pro897Leu	missense_variant	Exon 19 of 46	5		ENSP00000489777.1
CACNA1A	ENST00000636768.2	n.2690C>T		non_coding_transcript_exon_variant	Exon 19 of 45	5		ENSP00000490190.2
CACNA1A	ENST00000713789.1	n.2687C>T		non_coding_transcript_exon_variant	Exon 19 of 47			ENSP00000519091.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000564 AC: 12 AN: 212834 AF XY: 0.0000169

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000364

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000903 AC: 13 AN: 1439062 Hom.: 0 Cov.: 32 AF XY: 0.00000419 AC XY: 3 AN XY: 715762

African (AFR) AF: 0.00 AC: 0 AN: 33270

American (AMR) AF: 0.000297 AC: 13 AN: 43812

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25918

East Asian (EAS) AF: 0.00 AC: 0 AN: 39316

South Asian (SAS) AF: 0.00 AC: 0 AN: 85046

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 37990

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5594

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1108264

Other (OTH) AF: 0.00 AC: 0 AN: 59852

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000113

ExAC AF: 0.0000682 AC: 8

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Nov 13, 2023

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

Nov 05, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.086
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.21
CADD	Uncertain	23
DANN	Benign	0.79
DEOGEN2	Benign	0.030	.;.;T;.;.;.;.;.;.;T;.;.;.;T;.
Eigen	Benign	-0.60
Eigen_PC	Benign	-0.58
FATHMM_MKL	Benign	0.70	D
LIST_S2	Uncertain	0.91	D;D;D;D;D;D;D;D;.;D;D;D;D;D;D
M_CAP	Pathogenic	0.98	D
MetaRNN	Benign	0.19	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Uncertain	-0.029	T
MutationAssessor	Benign	1.1	.;.;.;.;L;.;.;.;.;.;.;.;L;.;.
PhyloP100		2.7
PrimateAI	Pathogenic	0.80	D
PROVEAN	Benign	-1.4	.;N;.;.;.;.;.;.;.;.;.;.;.;.;.
REVEL	Benign	0.25
Sift	Benign	0.12	.;T;.;.;.;.;.;.;.;.;.;.;.;.;.
Sift4G	Uncertain	0.046	D;D;.;.;.;.;.;.;.;.;.;.;.;.;.
Vest4		0.21
MutPred		0.15		.;.;Gain of catalytic residue at P897 (P = 0.1351);Gain of catalytic residue at P897 (P = 0.1351);Gain of catalytic residue at P897 (P = 0.1351);.;Gain of catalytic residue at P897 (P = 0.1351);.;.;Gain of catalytic residue at P897 (P = 0.1351);Gain of catalytic residue at P897 (P = 0.1351);.;Gain of catalytic residue at P897 (P = 0.1351);.;Gain of catalytic residue at P897 (P = 0.1351);
MVP		0.84
MPC		1.1
ClinPred		0.041	T
GERP RS		3.1
Varity_R		0.082
gMVP		0.65
Mutation Taster		=96/4	polymorphism

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

Other links and lift over

dbSNP: rs121908242; hg19: chr19-13409760;