rs1555740805

Variant names:

• chr19-13245235-C-G
• NM_001127222.2:c.4897G>C

Your query was ambiguous. Multiple possible variants found:

• chr19-13245235-C-G
• chr19-13245235-C-T

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM1 PM2 PM5 PP2 PP3_Strong

The NM_001127222.2(CACNA1A):​c.4897G>C​(p.Asp1633His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,640 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging 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. D1633N) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: CACNA1A NM_001127222.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.87

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 Pathogenic. Variant got 11 ACMG points.

• PM1: In a repeat IV (size 263) in uniprot entity CAC1A_HUMAN there are 14 pathogenic changes around while only 1 benign (93%) in NM_001127222.2
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr19-13245235-C-T is described in Lovd as [Likely_pathogenic].
• 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.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.987

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1A	NM_001127222.2	c.4897G>C	p.Asp1633His	missense_variant	Exon 31 of 47	ENST00000360228.11	NP_001120694.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CACNA1A	ENST00000360228.11	c.4897G>C	p.Asp1633His	missense_variant	Exon 31 of 47	1	NM_001127222.2	ENSP00000353362.5
CACNA1A	ENST00000638029.1	c.4909G>C	p.Asp1637His	missense_variant	Exon 31 of 48	5		ENSP00000489829.1
CACNA1A	ENST00000573710.7	c.4903G>C	p.Asp1635His	missense_variant	Exon 31 of 47	5		ENSP00000460092.3
CACNA1A	ENST00000635727.1	c.4900G>C	p.Asp1634His	missense_variant	Exon 31 of 47	5		ENSP00000490001.1
CACNA1A	ENST00000637769.1	c.4900G>C	p.Asp1634His	missense_variant	Exon 31 of 47	1		ENSP00000489778.1
CACNA1A	ENST00000636012.1	c.4900G>C	p.Asp1634His	missense_variant	Exon 31 of 46	5		ENSP00000490223.1
CACNA1A	ENST00000637736.1	c.4759G>C	p.Asp1587His	missense_variant	Exon 30 of 46	5		ENSP00000489861.1
CACNA1A	ENST00000636389.1	c.4900G>C	p.Asp1634His	missense_variant	Exon 31 of 47	5		ENSP00000489992.1
CACNA1A	ENST00000637432.1	c.4909G>C	p.Asp1637His	missense_variant	Exon 31 of 48	5		ENSP00000490617.1
CACNA1A	ENST00000636549.1	c.4900G>C	p.Asp1634His	missense_variant	Exon 31 of 48	5		ENSP00000490578.1
CACNA1A	ENST00000637927.1	c.4903G>C	p.Asp1635His	missense_variant	Exon 31 of 47	5		ENSP00000489715.1
CACNA1A	ENST00000635895.1	c.4900G>C	p.Asp1634His	missense_variant	Exon 31 of 47	5		ENSP00000490323.1
CACNA1A	ENST00000638009.2	c.4900G>C	p.Asp1634His	missense_variant	Exon 31 of 47	1		ENSP00000489913.1
CACNA1A	ENST00000637276.1	c.4900G>C	p.Asp1634His	missense_variant	Exon 31 of 46	5		ENSP00000489777.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461640 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727114

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.58	D
BayesDel_noAF	Pathogenic	0.59
CADD	Pathogenic	33
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.50	.;.;D;.;.;.;.;.;D;.;.;D;.;.;.;D;.;.;.
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.88
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D;D;D;D;D;D;D;D;D;D;.;D;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.95	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	0.94	D
MutationAssessor	Pathogenic	5.3	.;.;.;.;H;.;.;.;.;.;.;.;.;.;H;.;.;.;.
PrimateAI	Pathogenic	0.91	D
PROVEAN	Pathogenic	-6.7	.;D;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.
REVEL	Pathogenic	0.98
Sift	Pathogenic	0.0	.;D;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.
Sift4G	Pathogenic	0.0010	D;D;.;.;.;D;.;.;.;.;.;.;.;.;.;.;.;.;.
Vest4		0.98
MutPred		0.90		.;.;Loss of stability (P = 0.1348);Loss of stability (P = 0.1348);Loss of stability (P = 0.1348);.;.;Loss of stability (P = 0.1348);.;.;.;Loss of stability (P = 0.1348);Loss of stability (P = 0.1348);.;Loss of stability (P = 0.1348);.;.;Loss of stability (P = 0.1348);.;
MVP		0.98
MPC		2.6
ClinPred		1.0	D
GERP RS		4.7
Varity_R		0.90
gMVP		1.0

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr19-13356049;