rs757385012

Positions:

• chr19-13212111-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 3P and 3B. PM2 PP2 BP4 BP6_Moderate

The NM_001127222.2(CACNA1A):​c.6295G>A​(p.Glu2099Lys) variant causes a missense change. The variant allele was found at a frequency of 0.00000206 in 1,458,872 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: CACNA1A NM_001127222.2 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 5.72

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 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 0 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=0.34123933).
• BP6: Variant 19-13212111-C-T is Benign according to our data. Variant chr19-13212111-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 542821.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CACNA1A	NM_001127222.2	c.6295G>A	p.Glu2099Lys	missense_variant	43/47	ENST00000360228.11	NP_001120694.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CACNA1A	ENST00000360228.11	c.6295G>A	p.Glu2099Lys	missense_variant	43/47	1	NM_001127222.2	ENSP00000353362.5
CACNA1A	ENST00000638029.1	c.6313G>A	p.Glu2105Lys	missense_variant	44/48	5		ENSP00000489829.1
CACNA1A	ENST00000573710.7	c.6301G>A	p.Glu2101Lys	missense_variant	43/47	5		ENSP00000460092.3
CACNA1A	ENST00000635727.1	c.6298G>A	p.Glu2100Lys	missense_variant	43/47	5		ENSP00000490001.1
CACNA1A	ENST00000637769.1	c.6298G>A	p.Glu2100Lys	missense_variant	43/47	1		ENSP00000489778.1
CACNA1A	ENST00000636012.1	c.6298G>A	p.Glu2100Lys	missense_variant	43/46	5		ENSP00000490223.1
CACNA1A	ENST00000637736.1	c.6157G>A	p.Glu2053Lys	missense_variant	42/46	5		ENSP00000489861.1
CACNA1A	ENST00000636389.1	c.6298G>A	p.Glu2100Lys	missense_variant	43/47	5		ENSP00000489992.1
CACNA1A	ENST00000637432.1	c.6313G>A	p.Glu2105Lys	missense_variant	44/48	5		ENSP00000490617.1
CACNA1A	ENST00000636549.1	c.6304G>A	p.Glu2102Lys	missense_variant	44/48	5		ENSP00000490578.1
CACNA1A	ENST00000637927.1	c.6301G>A	p.Glu2101Lys	missense_variant	43/47	5		ENSP00000489715.1
CACNA1A	ENST00000635895.1	c.6298G>A	p.Glu2100Lys	missense_variant	43/47	5		ENSP00000490323.1
CACNA1A	ENST00000638009.2	c.6298G>A	p.Glu2100Lys	missense_variant	43/47	1		ENSP00000489913.1
CACNA1A	ENST00000637276.1	c.6298G>A	p.Glu2100Lys	missense_variant	43/46	5		ENSP00000489777.1
CACNA1A	ENST00000636768.1	n.*597G>A		non_coding_transcript_exon_variant	8/10	5		ENSP00000490190.2
CACNA1A	ENST00000636768.1	n.*597G>A		3_prime_UTR_variant	8/10	5		ENSP00000490190.2

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD3 exomes AF: 0.00000812 AC: 2 AN: 246438 Hom.: 0 AF XY: 0.00000746 AC XY: 1 AN XY: 134072

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000580

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: 0.00000206 AC: 3 AN: 1458872 Hom.: 0 Cov.: 31 AF XY: 0.00000276 AC XY: 2 AN XY: 725884

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.0000447

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 34

Bravo AF: 0.00000756

ExAC AF: 0.00000827 AC: 1

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Episodic ataxia type 2;C4310716:Developmental and epileptic encephalopathy, 42 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jul 11, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.70
BayesDel_addAF	Benign	-0.063	T
BayesDel_noAF	Benign	-0.15
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.096	.;.;T;.;.;.;.;.;T;.;.;T;.;.;.;T;.;.
Eigen	Benign	-0.11
Eigen_PC	Benign	-0.030
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Pathogenic	0.99	D;D;D;D;D;D;D;D;D;D;.;D;D;D;D;D;D;D
M_CAP	Uncertain	0.12	D
MetaRNN	Benign	0.34	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.36	T
MutationAssessor	Uncertain	2.0	.;.;.;.;M;.;.;.;.;.;.;.;.;.;M;.;.;.
PrimateAI	Pathogenic	0.85	D
PROVEAN	Uncertain	-3.3	.;D;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.
REVEL	Uncertain	0.32
Sift	Uncertain	0.0070	.;D;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.
Sift4G	Benign	0.23	T;T;.;.;.;D;.;.;.;.;.;.;.;.;.;.;.;.
Vest4		0.44
MutPred		0.30		.;.;Gain of methylation at E2100 (P = 0.0253);Gain of methylation at E2100 (P = 0.0253);Gain of methylation at E2100 (P = 0.0253);.;.;Gain of methylation at E2100 (P = 0.0253);.;.;.;Gain of methylation at E2100 (P = 0.0253);Gain of methylation at E2100 (P = 0.0253);.;Gain of methylation at E2100 (P = 0.0253);.;.;.;
MVP		0.79
MPC		0.59
ClinPred		0.67	D
GERP RS		3.4
Varity_R		0.35
gMVP		0.49

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: rs757385012; hg19: chr19-13322925;