19-13257499-C-T

Variant names:

• chr19-13257499-C-T
• rs121908232
• NM_001127222.2:c.4441G>A

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM1 PM2 PP3_Moderate

The NM_001127222.2(CACNA1A):​c.4441G>A​(p.Gly1481Arg) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as not provided (no stars). Synonymous variant affecting the same amino acid position (i.e. G1481G) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000028 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: CACNA1A NM_001127222.2 missense
• Clinical Significance: not provided no classification provided O:1
• Conservation: PhyloP100: 4.09
• Publications: 2 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_pathogenic. The variant received 6 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 uncertain in NM_001127222.2
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.914

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1A	NM_001127222.2	c.4441G>A	p.Gly1481Arg	missense_variant	Exon 28 of 47	ENST00000360228.11	NP_001120694.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CACNA1A	ENST00000360228.11	c.4441G>A	p.Gly1481Arg	missense_variant	Exon 28 of 47	1	NM_001127222.2	ENSP00000353362.5
CACNA1A	ENST00000638029.1	c.4453G>A	p.Gly1485Arg	missense_variant	Exon 28 of 48	5		ENSP00000489829.1
CACNA1A	ENST00000573710.7	c.4447G>A	p.Gly1483Arg	missense_variant	Exon 28 of 47	5		ENSP00000460092.3
CACNA1A	ENST00000635727.1	c.4444G>A	p.Gly1482Arg	missense_variant	Exon 28 of 47	5		ENSP00000490001.1
CACNA1A	ENST00000637769.1	c.4444G>A	p.Gly1482Arg	missense_variant	Exon 28 of 47	1		ENSP00000489778.1
CACNA1A	ENST00000636012.1	c.4444G>A	p.Gly1482Arg	missense_variant	Exon 28 of 46	5		ENSP00000490223.1
CACNA1A	ENST00000637736.1	c.4303G>A	p.Gly1435Arg	missense_variant	Exon 27 of 46	5		ENSP00000489861.1
CACNA1A	ENST00000636389.1	c.4444G>A	p.Gly1482Arg	missense_variant	Exon 28 of 47	5		ENSP00000489992.1
CACNA1A	ENST00000637432.1	c.4453G>A	p.Gly1485Arg	missense_variant	Exon 28 of 48	5		ENSP00000490617.1
CACNA1A	ENST00000636549.1	c.4444G>A	p.Gly1482Arg	missense_variant	Exon 28 of 48	5		ENSP00000490578.1
CACNA1A	ENST00000637927.1	c.4447G>A	p.Gly1483Arg	missense_variant	Exon 28 of 47	5		ENSP00000489715.1
CACNA1A	ENST00000635895.1	c.4444G>A	p.Gly1482Arg	missense_variant	Exon 28 of 47	5		ENSP00000490323.1
CACNA1A	ENST00000638009.2	c.4444G>A	p.Gly1482Arg	missense_variant	Exon 28 of 47	1		ENSP00000489913.1
CACNA1A	ENST00000637276.1	c.4444G>A	p.Gly1482Arg	missense_variant	Exon 28 of 46	5		ENSP00000489777.1
CACNA1A	ENST00000636768.2	n.4444G>A		non_coding_transcript_exon_variant	Exon 28 of 45	5		ENSP00000490190.2
CACNA1A	ENST00000713789.1	n.4441G>A		non_coding_transcript_exon_variant	Exon 28 of 47			ENSP00000519091.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000430 AC: 1 AN: 232438 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000961

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000275 AC: 4 AN: 1453702 Hom.: 0 Cov.: 31 AF XY: 0.00000277 AC XY: 2 AN XY: 722352

African (AFR) AF: 0.00 AC: 0 AN: 33376

American (AMR) AF: 0.00 AC: 0 AN: 42884

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25964

East Asian (EAS) AF: 0.0000253 AC: 1 AN: 39498

South Asian (SAS) AF: 0.00 AC: 0 AN: 85236

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53020

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5762

European-Non Finnish (NFE) AF: 0.00000271 AC: 3 AN: 1107810

Other (OTH) AF: 0.00 AC: 0 AN: 60152

GnomAD4 genome Cov.: 32

ClinVar

Significance: not provided

Submissions summary: Other:1

Revision: no classification provided

Submissions by phenotype

Episodic ataxia type 2 Other:1

-

UniProtKB/Swiss-Prot

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.50	D
BayesDel_noAF	Pathogenic	0.48
CADD	Pathogenic	33
DANN	Uncertain	1.0
DEOGEN2	Benign	0.13	.;.;T;.;.;.;.;.;.;T;.;.;.;T;.;.
Eigen	Uncertain	0.57
Eigen_PC	Uncertain	0.54
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Uncertain	0.96	D;D;D;D;D;D;D;D;.;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.83	D
MetaRNN	Pathogenic	0.91	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.2	.;.;.;.;M;.;.;.;.;.;.;.;M;.;.;.
PhyloP100		4.1
PrimateAI	Pathogenic	0.81	D
PROVEAN	Pathogenic	-7.5	.;D;.;.;.;.;.;.;.;.;.;.;.;.;.;.
REVEL	Pathogenic	0.78
Sift	Uncertain	0.0040	.;D;.;.;.;.;.;.;.;.;.;.;.;.;.;.
Sift4G	Uncertain	0.010	D;D;.;.;.;.;.;.;.;.;.;.;.;.;.;.
Vest4		0.81
MutPred		0.63		.;.;Gain of helix (P = 0.0854);Gain of helix (P = 0.0854);Gain of helix (P = 0.0854);.;Gain of helix (P = 0.0854);.;.;Gain of helix (P = 0.0854);Gain of helix (P = 0.0854);.;Gain of helix (P = 0.0854);.;Gain of helix (P = 0.0854);.;
MVP		0.99
MPC		2.6
ClinPred		0.99	D
GERP RS		5.1
PromoterAI		0.043	Neutral
Varity_R		0.60
gMVP		0.97
Mutation Taster		=3/97	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.19		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: rs121908232; hg19: chr19-13368313;