rs368081042

Positions:

• chr19-13298884-C-G
• chr19-13298884-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2 PP2 BP4_Moderate

The NM_001127222.2(CACNA1A):​c.2749G>C​(p.Glu917Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000188 in 1,593,836 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 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. E917D) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: CACNA1A NM_001127222.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.412

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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), CACNA1A. . Gene score misZ 5.7845 (greater than the threshold 3.09). Trascript score misZ 3.9354 (greater than threshold 3.09). GenCC has associacion of gene with 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.
• BP4: Computational evidence support a benign effect (MetaRNN=0.26157102).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CACNA1A	NM_001127222.2	c.2749G>C	p.Glu917Gln	missense_variant	19/47	ENST00000360228.11	NP_001120694.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CACNA1A	ENST00000360228.11	c.2749G>C	p.Glu917Gln	missense_variant	19/47	1	NM_001127222.2	ENSP00000353362.5
CACNA1A	ENST00000638029.1	c.2761G>C	p.Glu921Gln	missense_variant	19/48	5		ENSP00000489829.1
CACNA1A	ENST00000573710.7	c.2755G>C	p.Glu919Gln	missense_variant	19/47	5		ENSP00000460092.3
CACNA1A	ENST00000635727.1	c.2752G>C	p.Glu918Gln	missense_variant	19/47	5		ENSP00000490001.1
CACNA1A	ENST00000637769.1	c.2752G>C	p.Glu918Gln	missense_variant	19/47	1		ENSP00000489778.1
CACNA1A	ENST00000636012.1	c.2752G>C	p.Glu918Gln	missense_variant	19/46	5		ENSP00000490223.1
CACNA1A	ENST00000637736.1	c.2611G>C	p.Glu871Gln	missense_variant	18/46	5		ENSP00000489861.1
CACNA1A	ENST00000636389.1	c.2752G>C	p.Glu918Gln	missense_variant	19/47	5		ENSP00000489992.1
CACNA1A	ENST00000637432.1	c.2761G>C	p.Glu921Gln	missense_variant	19/48	5		ENSP00000490617.1
CACNA1A	ENST00000636549.1	c.2752G>C	p.Glu918Gln	missense_variant	19/48	5		ENSP00000490578.1
CACNA1A	ENST00000637927.1	c.2755G>C	p.Glu919Gln	missense_variant	19/47	5		ENSP00000489715.1
CACNA1A	ENST00000635895.1	c.2752G>C	p.Glu918Gln	missense_variant	19/47	5		ENSP00000490323.1
CACNA1A	ENST00000638009.2	c.2752G>C	p.Glu918Gln	missense_variant	19/47	1		ENSP00000489913.1
CACNA1A	ENST00000637276.1	c.2752G>C	p.Glu918Gln	missense_variant	19/46	5		ENSP00000489777.1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152200 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00000459 AC: 1 AN: 217642 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 121384

Gnomad AFR exome AF: 0.0000787

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000139 AC: 2 AN: 1441636 Hom.: 0 Cov.: 32 AF XY: 0.00000139 AC XY: 1 AN XY: 717476

Gnomad4 AFR exome AF: 0.0000302

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: 9.01e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152200 Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1 AN XY: 74352

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000189

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.29
CADD	Benign	20
DANN	Benign	0.77
DEOGEN2	Benign	0.020	.;.;T;.;.;.;.;.;.;T;.;.;.;T;.
Eigen	Benign	-0.27
Eigen_PC	Benign	-0.23
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Benign	0.73	T;T;T;T;T;T;T;T;.;T;T;T;T;T;T
M_CAP	Pathogenic	0.89	D
MetaRNN	Benign	0.26	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Uncertain	0.37	D
MutationAssessor	Benign	1.2	.;.;.;.;L;.;.;.;.;.;.;.;L;.;.
PrimateAI	Uncertain	0.76	T
PROVEAN	Benign	-0.79	.;N;.;.;.;.;.;.;.;.;.;.;.;.;.
REVEL	Uncertain	0.30
Sift	Benign	0.13	.;T;.;.;.;.;.;.;.;.;.;.;.;.;.
Sift4G	Benign	0.21	T;T;.;.;.;.;.;.;.;.;.;.;.;.;.
Vest4		0.073
MutPred		0.20		.;.;Gain of MoRF binding (P = 0.0499);Gain of MoRF binding (P = 0.0499);Gain of MoRF binding (P = 0.0499);.;Gain of MoRF binding (P = 0.0499);.;.;Gain of MoRF binding (P = 0.0499);Gain of MoRF binding (P = 0.0499);.;Gain of MoRF binding (P = 0.0499);.;Gain of MoRF binding (P = 0.0499);
MVP		0.89
MPC		2.1
ClinPred		0.23	T
GERP RS		2.7
Varity_R		0.061
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: rs368081042; hg19: chr19-13409698;