rs769040794

Variant names:

• chr19-13212203-C-G
• rs769040794
• NM_001127222.2:c.6203G>C

Your query was ambiguous. Multiple possible variants found:

• chr19-13212203-C-G
• chr19-13212203-C-T

Variant summary

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

The ENST00000360228.11(CACNA1A):​c.6203G>C​(p.Arg2068Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000186 in 1,613,714 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. R2068Q) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 34)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: CACNA1A ENST00000360228.11 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.83

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.6203G>C	p.Arg2068Pro	missense_variant	Exon 43 of 47	ENST00000360228.11	NP_001120694.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CACNA1A	ENST00000360228.11	c.6203G>C	p.Arg2068Pro	missense_variant	Exon 43 of 47	1	NM_001127222.2	ENSP00000353362.5
CACNA1A	ENST00000638029.1	c.6221G>C	p.Arg2074Pro	missense_variant	Exon 44 of 48	5		ENSP00000489829.1
CACNA1A	ENST00000573710.7	c.6209G>C	p.Arg2070Pro	missense_variant	Exon 43 of 47	5		ENSP00000460092.3
CACNA1A	ENST00000635727.1	c.6206G>C	p.Arg2069Pro	missense_variant	Exon 43 of 47	5		ENSP00000490001.1
CACNA1A	ENST00000637769.1	c.6206G>C	p.Arg2069Pro	missense_variant	Exon 43 of 47	1		ENSP00000489778.1
CACNA1A	ENST00000636012.1	c.6206G>C	p.Arg2069Pro	missense_variant	Exon 43 of 46	5		ENSP00000490223.1
CACNA1A	ENST00000637736.1	c.6065G>C	p.Arg2022Pro	missense_variant	Exon 42 of 46	5		ENSP00000489861.1
CACNA1A	ENST00000636389.1	c.6206G>C	p.Arg2069Pro	missense_variant	Exon 43 of 47	5		ENSP00000489992.1
CACNA1A	ENST00000637432.1	c.6221G>C	p.Arg2074Pro	missense_variant	Exon 44 of 48	5		ENSP00000490617.1
CACNA1A	ENST00000636549.1	c.6212G>C	p.Arg2071Pro	missense_variant	Exon 44 of 48	5		ENSP00000490578.1
CACNA1A	ENST00000637927.1	c.6209G>C	p.Arg2070Pro	missense_variant	Exon 43 of 47	5		ENSP00000489715.1
CACNA1A	ENST00000635895.1	c.6206G>C	p.Arg2069Pro	missense_variant	Exon 43 of 47	5		ENSP00000490323.1
CACNA1A	ENST00000638009.2	c.6206G>C	p.Arg2069Pro	missense_variant	Exon 43 of 47	1		ENSP00000489913.1
CACNA1A	ENST00000637276.1	c.6206G>C	p.Arg2069Pro	missense_variant	Exon 43 of 46	5		ENSP00000489777.1
CACNA1A	ENST00000636768.1	n.*505G>C		non_coding_transcript_exon_variant	Exon 8 of 10	5		ENSP00000490190.2
CACNA1A	ENST00000636768.1	n.*505G>C		3_prime_UTR_variant	Exon 8 of 10	5		ENSP00000490190.2

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152220 Hom.: 0 Cov.: 34

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: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461494 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 727066

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.00e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152220 Hom.: 0 Cov.: 34 AF XY: 0.00 AC XY: 0 AN XY: 74362

Gnomad4 AFR AF: 0.00

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: 0.0000147

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.38
BayesDel_addAF	Pathogenic	0.26	D
BayesDel_noAF	Pathogenic	0.14
CADD	Uncertain	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.077	.;.;T;.;.;.;.;.;T;.;.;T;.;.;.;T;.;.
Eigen	Benign	0.017
Eigen_PC	Benign	0.0032
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Uncertain	0.96	D;D;D;D;D;D;D;D;D;D;.;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.31	D
MetaRNN	Uncertain	0.70	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Benign	-0.44	T
MutationAssessor	Uncertain	2.3	.;.;.;.;M;.;.;.;.;.;.;.;.;.;M;.;.;.
PrimateAI	Uncertain	0.55	T
PROVEAN	Pathogenic	-4.9	.;D;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.
REVEL	Uncertain	0.51
Sift	Uncertain	0.0070	.;D;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.
Sift4G	Benign	0.097	T;T;.;.;.;T;.;.;.;.;.;.;.;.;.;.;.;.
Vest4		0.66
MutPred		0.21		.;.;Gain of glycosylation at S2065 (P = 0.1008);Gain of glycosylation at S2065 (P = 0.1008);Gain of glycosylation at S2065 (P = 0.1008);.;.;Gain of glycosylation at S2065 (P = 0.1008);.;.;.;Gain of glycosylation at S2065 (P = 0.1008);Gain of glycosylation at S2065 (P = 0.1008);.;Gain of glycosylation at S2065 (P = 0.1008);.;.;.;
MVP		0.93
MPC		0.85
ClinPred		0.99	D
GERP RS		3.4
Varity_R		0.72
gMVP		0.58

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: rs769040794; hg19: chr19-13323017;