rs267605294

Variant names:

• chr19-13231774-C-A
• rs267605294
• NM_001127222.2:c.5336G>T

Your query was ambiguous. Multiple possible variants found:

• chr19-13231774-C-A
• chr19-13231774-C-T

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 2P and 6B. PM1 BP4_Moderate BS2

The NM_001127222.2(CACNA1A):​c.5336G>T​(p.Arg1779Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000616 in 1,461,556 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1779Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000062 (0 hom.)
• Consequence: CACNA1A NM_001127222.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.02
• Publications: 0 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: Likely_benign. The variant received -4 ACMG points.

• PM1: In a repeat IV (size 263) in uniprot entity CAC1A_HUMAN there are 39 pathogenic changes around while only 10 benign (80%) in NM_001127222.2
• BP4: Computational evidence support a benign effect (MetaRNN=0.22133031).
• BS2: High AC in GnomAdExome4 at 9 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1A	NM_001127222.2	c.5336G>T	p.Arg1779Leu	missense_variant	Exon 35 of 47	ENST00000360228.11	NP_001120694.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CACNA1A	ENST00000360228.11	c.5336G>T	p.Arg1779Leu	missense_variant	Exon 35 of 47	1	NM_001127222.2	ENSP00000353362.5
CACNA1A	ENST00000638029.1	c.5354G>T	p.Arg1785Leu	missense_variant	Exon 36 of 48	5		ENSP00000489829.1
CACNA1A	ENST00000573710.7	c.5342G>T	p.Arg1781Leu	missense_variant	Exon 35 of 47	5		ENSP00000460092.3
CACNA1A	ENST00000635727.1	c.5339G>T	p.Arg1780Leu	missense_variant	Exon 35 of 47	5		ENSP00000490001.1
CACNA1A	ENST00000637769.1	c.5339G>T	p.Arg1780Leu	missense_variant	Exon 35 of 47	1		ENSP00000489778.1
CACNA1A	ENST00000636012.1	c.5339G>T	p.Arg1780Leu	missense_variant	Exon 35 of 46	5		ENSP00000490223.1
CACNA1A	ENST00000637736.1	c.5198G>T	p.Arg1733Leu	missense_variant	Exon 34 of 46	5		ENSP00000489861.1
CACNA1A	ENST00000636389.1	c.5339G>T	p.Arg1780Leu	missense_variant	Exon 35 of 47	5		ENSP00000489992.1
CACNA1A	ENST00000637432.1	c.5354G>T	p.Arg1785Leu	missense_variant	Exon 36 of 48	5		ENSP00000490617.1
CACNA1A	ENST00000636549.1	c.5345G>T	p.Arg1782Leu	missense_variant	Exon 36 of 48	5		ENSP00000490578.1
CACNA1A	ENST00000637927.1	c.5342G>T	p.Arg1781Leu	missense_variant	Exon 35 of 47	5		ENSP00000489715.1
CACNA1A	ENST00000635895.1	c.5339G>T	p.Arg1780Leu	missense_variant	Exon 35 of 47	5		ENSP00000490323.1
CACNA1A	ENST00000638009.2	c.5339G>T	p.Arg1780Leu	missense_variant	Exon 35 of 47	1		ENSP00000489913.1
CACNA1A	ENST00000637276.1	c.5339G>T	p.Arg1780Leu	missense_variant	Exon 35 of 46	5		ENSP00000489777.1
CACNA1A	ENST00000636768.2	n.5339G>T		non_coding_transcript_exon_variant	Exon 35 of 45	5		ENSP00000490190.2
CACNA1A	ENST00000713789.1	n.*517G>T		non_coding_transcript_exon_variant	Exon 36 of 47			ENSP00000519091.1
CACNA1A	ENST00000713789.1	n.*517G>T		3_prime_UTR_variant	Exon 36 of 47			ENSP00000519091.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000616 AC: 9 AN: 1461556 Hom.: 0 Cov.: 31 AF XY: 0.00000550 AC XY: 4 AN XY: 727052

African (AFR) AF: 0.00 AC: 0 AN: 33472

American (AMR) AF: 0.00 AC: 0 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86244

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53402

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.00000810 AC: 9 AN: 1111768

Other (OTH) AF: 0.00 AC: 0 AN: 60358

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Uncertain	0.048	T
BayesDel_noAF	Benign	-0.17
CADD	Benign	22
DANN	Benign	0.93
DEOGEN2	Benign	0.062	.;.;T;.;.;.;.;.;D;.;.;T;.;.;.;T;.;.;.;.
Eigen	Benign	-0.68
Eigen_PC	Benign	-0.65
FATHMM_MKL	Benign	0.17	N
LIST_S2	Uncertain	0.92	D;D;D;D;D;D;D;D;D;D;.;D;D;D;D;D;D;D;D;D
M_CAP	Uncertain	0.14	D
MetaRNN	Benign	0.22	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Uncertain	-0.046	T
MutationAssessor	Benign	0.78	.;.;.;.;N;.;.;.;.;.;.;.;.;.;N;.;.;.;.;.
PhyloP100		2.0
PrimateAI	Benign	0.31	T
PROVEAN	Uncertain	-2.6	.;D;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.
REVEL	Benign	0.21
Sift	Benign	0.23	.;T;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.
Sift4G	Benign	0.29	T;T;.;.;.;T;.;.;.;.;.;.;.;.;.;.;.;.;.;.
Vest4		0.13
MutPred		0.68		.;.;Loss of catalytic residue at R1780 (P = 0.0931);Loss of catalytic residue at R1780 (P = 0.0931);Loss of catalytic residue at R1780 (P = 0.0931);.;.;Loss of catalytic residue at R1780 (P = 0.0931);.;.;.;Loss of catalytic residue at R1780 (P = 0.0931);Loss of catalytic residue at R1780 (P = 0.0931);.;Loss of catalytic residue at R1780 (P = 0.0931);.;.;.;.;.;
MVP		0.79
MPC		1.5
ClinPred		0.13	T
GERP RS		2.6
Varity_R		0.090
gMVP		0.65
Mutation Taster		=93/7	polymorphism

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

Other links and lift over

dbSNP: rs267605294; hg19: chr19-13342588;