rs760904322

Variant names:

• chr19-13207377-C-A
• rs760904322
• NM_001127222.2:c.7457G>T

Your query was ambiguous. Multiple possible variants found:

• chr19-13207377-C-A
• chr19-13207377-C-T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001127222.2(CACNA1A):​c.7457G>T​(p.Arg2486Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000717 in 1,394,638 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts 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. R2486H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 7.2e-7 (0 hom.)
• Consequence: CACNA1A NM_001127222.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.44
• 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

ENSG00000300728 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.28315488).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1A	NM_001127222.2	c.7457G>T	p.Arg2486Leu	missense_variant	Exon 47 of 47	ENST00000360228.11	NP_001120694.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CACNA1A	ENST00000360228.11	c.7457G>T	p.Arg2486Leu	missense_variant	Exon 47 of 47	1	NM_001127222.2	ENSP00000353362.5
CACNA1A	ENST00000638029.1	c.7475G>T	p.Arg2492Leu	missense_variant	Exon 48 of 48	5		ENSP00000489829.1
CACNA1A	ENST00000573710.7	c.7463G>T	p.Arg2488Leu	missense_variant	Exon 47 of 47	5		ENSP00000460092.3
CACNA1A	ENST00000635727.1	c.7460G>T	p.Arg2487Leu	missense_variant	Exon 47 of 47	5		ENSP00000490001.1
CACNA1A	ENST00000637769.1	c.7460G>T	p.Arg2487Leu	missense_variant	Exon 47 of 47	1		ENSP00000489778.1
CACNA1A	ENST00000636012.1	c.7424G>T	p.Arg2475Leu	missense_variant	Exon 46 of 46	5		ENSP00000490223.1
CACNA1A	ENST00000637736.1	c.7319G>T	p.Arg2440Leu	missense_variant	Exon 46 of 46	5		ENSP00000489861.1
CACNA1A	ENST00000636768.2	n.*1718G>T		non_coding_transcript_exon_variant	Exon 45 of 45	5		ENSP00000490190.2
CACNA1A	ENST00000713789.1	n.*2636G>T		non_coding_transcript_exon_variant	Exon 47 of 47			ENSP00000519091.1
CACNA1A	ENST00000636389.1	c.*543G>T		3_prime_UTR_variant	Exon 47 of 47	5		ENSP00000489992.1
CACNA1A	ENST00000637432.1	c.*669G>T		3_prime_UTR_variant	Exon 48 of 48	5		ENSP00000490617.1
CACNA1A	ENST00000635895.1	c.*669G>T		3_prime_UTR_variant	Exon 47 of 47	5		ENSP00000490323.1
CACNA1A	ENST00000638009.2	c.*669G>T		3_prime_UTR_variant	Exon 47 of 47	1		ENSP00000489913.1
CACNA1A	ENST00000636768.2	n.*1718G>T		3_prime_UTR_variant	Exon 45 of 45	5		ENSP00000490190.2
CACNA1A	ENST00000713789.1	n.*2636G>T		3_prime_UTR_variant	Exon 47 of 47			ENSP00000519091.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 7.17e-7 AC: 1 AN: 1394638 Hom.: 0 Cov.: 30 AF XY: 0.00000145 AC XY: 1 AN XY: 690672

African (AFR) AF: 0.00 AC: 0 AN: 31626

American (AMR) AF: 0.0000266 AC: 1 AN: 37654

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24984

East Asian (EAS) AF: 0.00 AC: 0 AN: 36394

South Asian (SAS) AF: 0.00 AC: 0 AN: 80826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 34662

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5668

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1084848

Other (OTH) AF: 0.00 AC: 0 AN: 57976

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.23
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Uncertain	-0.080
CADD	Benign	23
DANN	Uncertain	0.98
DEOGEN2	Benign	0.024	.;.;T;.;.;T;.;T;.;.
Eigen	Benign	-0.54
Eigen_PC	Benign	-0.58
FATHMM_MKL	Benign	0.072	N
LIST_S2	Benign	0.85	T;T;T;T;T;T;.;T;T;T
M_CAP	Pathogenic	0.97	D
MetaRNN	Benign	0.28	T;T;T;T;T;T;T;T;T;T
MetaSVM	Uncertain	0.15	D
PhyloP100		2.4
PrimateAI	Pathogenic	0.91	D
PROVEAN	Benign	-1.9	.;N;.;.;.;.;.;.;.;.
REVEL	Uncertain	0.34
Sift	Benign	0.59	.;T;.;.;.;.;.;.;.;.
Sift4G	Benign	0.30	T;T;.;T;.;.;.;.;.;.
Vest4		0.17
MutPred		0.37		.;Loss of solvent accessibility (P = 3e-04);.;.;.;.;.;.;.;.;
MVP		0.84
MPC		0.60
ClinPred		0.32	T
GERP RS		2.1
Varity_R		0.060
gMVP		0.27
Mutation Taster		=92/8	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: rs760904322; hg19: chr19-13318191;