19-13212448-G-C

Variant names:

• chr19-13212448-G-C
• rs563345694
• NM_001127222.2:c.6125C>G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP2

The NM_001127222.2(CACNA1A):​c.6125C>G​(p.Thr2042Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,144 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. T2042T) has been classified as Benign.

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
• Consequence: CACNA1A NM_001127222.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.59

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 Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the CACNA1A gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 137 curated pathogenic missense variants (we use a threshold of 10). The gene has 132 curated benign missense variants. Gene score misZ: 5.7845 (above the threshold of 3.09). Trascript score misZ: 3.9354 (above the threshold of 3.09). GenCC associations: The gene is linked to 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1A	NM_001127222.2	c.6125C>G	p.Thr2042Arg	missense_variant	Exon 42 of 47	ENST00000360228.11	NP_001120694.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CACNA1A	ENST00000360228.11	c.6125C>G	p.Thr2042Arg	missense_variant	Exon 42 of 47	1	NM_001127222.2	ENSP00000353362.5
CACNA1A	ENST00000638029.1	c.6143C>G	p.Thr2048Arg	missense_variant	Exon 43 of 48	5		ENSP00000489829.1
CACNA1A	ENST00000573710.7	c.6131C>G	p.Thr2044Arg	missense_variant	Exon 42 of 47	5		ENSP00000460092.3
CACNA1A	ENST00000635727.1	c.6128C>G	p.Thr2043Arg	missense_variant	Exon 42 of 47	5		ENSP00000490001.1
CACNA1A	ENST00000637769.1	c.6128C>G	p.Thr2043Arg	missense_variant	Exon 42 of 47	1		ENSP00000489778.1
CACNA1A	ENST00000636012.1	c.6128C>G	p.Thr2043Arg	missense_variant	Exon 42 of 46	5		ENSP00000490223.1
CACNA1A	ENST00000637736.1	c.5987C>G	p.Thr1996Arg	missense_variant	Exon 41 of 46	5		ENSP00000489861.1
CACNA1A	ENST00000636389.1	c.6128C>G	p.Thr2043Arg	missense_variant	Exon 42 of 47	5		ENSP00000489992.1
CACNA1A	ENST00000637432.1	c.6143C>G	p.Thr2048Arg	missense_variant	Exon 43 of 48	5		ENSP00000490617.1
CACNA1A	ENST00000636549.1	c.6134C>G	p.Thr2045Arg	missense_variant	Exon 43 of 48	5		ENSP00000490578.1
CACNA1A	ENST00000637927.1	c.6131C>G	p.Thr2044Arg	missense_variant	Exon 42 of 47	5		ENSP00000489715.1
CACNA1A	ENST00000635895.1	c.6128C>G	p.Thr2043Arg	missense_variant	Exon 42 of 47	5		ENSP00000490323.1
CACNA1A	ENST00000638009.2	c.6128C>G	p.Thr2043Arg	missense_variant	Exon 42 of 47	1		ENSP00000489913.1
CACNA1A	ENST00000637276.1	c.6128C>G	p.Thr2043Arg	missense_variant	Exon 42 of 46	5		ENSP00000489777.1
CACNA1A	ENST00000636768.1	n.*427C>G		non_coding_transcript_exon_variant	Exon 7 of 10	5		ENSP00000490190.2
CACNA1A	ENST00000636768.1	n.*427C>G		3_prime_UTR_variant	Exon 7 of 10	5		ENSP00000490190.2

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152144 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 34

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152144 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74308

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.30
BayesDel_addAF	Pathogenic	0.35	D
BayesDel_noAF	Pathogenic	0.26
CADD	Uncertain	25
DANN	Benign	0.93
DEOGEN2	Benign	0.031	.;.;T;.;.;.;.;.;T;.;.;T;.;.;.;T;.;.
Eigen	Uncertain	0.19
Eigen_PC	Benign	0.20
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.97	D;D;D;D;D;D;D;D;D;D;.;D;D;D;D;D;D;D
M_CAP	Uncertain	0.20	D
MetaRNN	Uncertain	0.69	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.66	D
MutationAssessor	Uncertain	2.4	.;.;.;.;M;.;.;.;.;.;.;.;.;.;M;.;.;.
PrimateAI	Pathogenic	0.81	D
PROVEAN	Uncertain	-3.3	.;D;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.
REVEL	Pathogenic	0.67
Sift	Uncertain	0.029	.;D;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.
Sift4G	Benign	0.53	T;T;.;.;.;T;.;.;.;.;.;.;.;.;.;.;.;.
Vest4		0.62
MutPred		0.36		.;.;Gain of solvent accessibility (P = 0.0058);Gain of solvent accessibility (P = 0.0058);Gain of solvent accessibility (P = 0.0058);.;.;Gain of solvent accessibility (P = 0.0058);.;.;.;Gain of solvent accessibility (P = 0.0058);Gain of solvent accessibility (P = 0.0058);.;Gain of solvent accessibility (P = 0.0058);.;.;.;
MVP		0.95
MPC		0.85
ClinPred		0.94	D
GERP RS		3.6
Varity_R		0.23
gMVP		0.47

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: rs563345694; hg19: chr19-13323262;