rs765300713

Positions:

• chr19-13298926-G-A

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.2707C>T​(p.His903Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000314 in 1,594,172 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: CACNA1A NM_001127222.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.239

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). The gene has 137 curated pathogenic missense variants (we use a threshold of 10). The gene has 132 curated benign missense variants. GenCC has associacion of the 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=0.16728655).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CACNA1A	NM_001127222.2	c.2707C>T	p.His903Tyr	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.2707C>T	p.His903Tyr	missense_variant	19/47	1	NM_001127222.2	ENSP00000353362.5
CACNA1A	ENST00000638029.1	c.2719C>T	p.His907Tyr	missense_variant	19/48	5		ENSP00000489829.1
CACNA1A	ENST00000573710.7	c.2713C>T	p.His905Tyr	missense_variant	19/47	5		ENSP00000460092.3
CACNA1A	ENST00000635727.1	c.2710C>T	p.His904Tyr	missense_variant	19/47	5		ENSP00000490001.1
CACNA1A	ENST00000637769.1	c.2710C>T	p.His904Tyr	missense_variant	19/47	1		ENSP00000489778.1
CACNA1A	ENST00000636012.1	c.2710C>T	p.His904Tyr	missense_variant	19/46	5		ENSP00000490223.1
CACNA1A	ENST00000637736.1	c.2569C>T	p.His857Tyr	missense_variant	18/46	5		ENSP00000489861.1
CACNA1A	ENST00000636389.1	c.2710C>T	p.His904Tyr	missense_variant	19/47	5		ENSP00000489992.1
CACNA1A	ENST00000637432.1	c.2719C>T	p.His907Tyr	missense_variant	19/48	5		ENSP00000490617.1
CACNA1A	ENST00000636549.1	c.2710C>T	p.His904Tyr	missense_variant	19/48	5		ENSP00000490578.1
CACNA1A	ENST00000637927.1	c.2713C>T	p.His905Tyr	missense_variant	19/47	5		ENSP00000489715.1
CACNA1A	ENST00000635895.1	c.2710C>T	p.His904Tyr	missense_variant	19/47	5		ENSP00000490323.1
CACNA1A	ENST00000638009.2	c.2710C>T	p.His904Tyr	missense_variant	19/47	1		ENSP00000489913.1
CACNA1A	ENST00000637276.1	c.2710C>T	p.His904Tyr	missense_variant	19/46	5		ENSP00000489777.1

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152202 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: 0.000193

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

GnomAD3 exomes AF: 0.0000184 AC: 4 AN: 217426 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 121218

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 SAS exome AF: 0.000136

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000208 AC: 3 AN: 1441970 Hom.: 0 Cov.: 32 AF XY: 0.00000139 AC XY: 1 AN XY: 717566

Gnomad4 AFR exome AF: 0.0000300

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000234

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152202 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74344

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000378

ExAC AF: 0.00000852 AC: 1

Asia WGS AF: 0.000289 AC: 1 AN: 3468

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Athena Diagnostics

Dec 27, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.082
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.30
CADD	Benign	17
DANN	Benign	0.76
DEOGEN2	Benign	0.035	.;.;T;.;.;.;.;.;.;T;.;.;.;T;.
Eigen	Benign	-1.0
Eigen_PC	Benign	-0.90
FATHMM_MKL	Benign	0.23	N
LIST_S2	Benign	0.75	T;T;T;T;T;T;T;T;.;T;T;T;T;T;T
M_CAP	Pathogenic	0.97	D
MetaRNN	Benign	0.17	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Uncertain	-0.091	T
MutationAssessor	Benign	0.90	.;.;.;.;L;.;.;.;.;.;.;.;L;.;.
PrimateAI	Pathogenic	0.83	D
PROVEAN	Benign	-2.1	.;N;.;.;.;.;.;.;.;.;.;.;.;.;.
REVEL	Benign	0.28
Sift	Benign	0.22	.;T;.;.;.;.;.;.;.;.;.;.;.;.;.
Sift4G	Benign	0.36	T;T;.;.;.;.;.;.;.;.;.;.;.;.;.
Vest4		0.097
MutPred		0.20		.;.;Gain of phosphorylation at H904 (P = 0.0073);Gain of phosphorylation at H904 (P = 0.0073);Gain of phosphorylation at H904 (P = 0.0073);.;Gain of phosphorylation at H904 (P = 0.0073);.;.;Gain of phosphorylation at H904 (P = 0.0073);Gain of phosphorylation at H904 (P = 0.0073);.;Gain of phosphorylation at H904 (P = 0.0073);.;Gain of phosphorylation at H904 (P = 0.0073);
MVP		0.59
MPC		1.4
ClinPred		0.030	T
GERP RS		2.3
Varity_R		0.10
gMVP		0.67

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: rs765300713; hg19: chr19-13409740;