rs755749925

Variant names:

• chr19-13209371-C-A
• rs755749925
• NM_001127222.2:c.6467G>T

Your query was ambiguous. Multiple possible variants found:

• chr19-13209371-C-A
• chr19-13209371-C-T

Variant summary

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

The NM_001127222.2(CACNA1A):​c.6467G>T​(p.Arg2156Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00000657 in 152,160 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: CACNA1A NM_001127222.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.95

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.6467G>T	p.Arg2156Leu	missense_variant	Exon 45 of 47	ENST00000360228.11	NP_001120694.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CACNA1A	ENST00000360228.11	c.6467G>T	p.Arg2156Leu	missense_variant	Exon 45 of 47	1	NM_001127222.2	ENSP00000353362.5
CACNA1A	ENST00000638029.1	c.6485G>T	p.Arg2162Leu	missense_variant	Exon 46 of 48	5		ENSP00000489829.1
CACNA1A	ENST00000573710.7	c.6473G>T	p.Arg2158Leu	missense_variant	Exon 45 of 47	5		ENSP00000460092.3
CACNA1A	ENST00000635727.1	c.6470G>T	p.Arg2157Leu	missense_variant	Exon 45 of 47	5		ENSP00000490001.1
CACNA1A	ENST00000637769.1	c.6470G>T	p.Arg2157Leu	missense_variant	Exon 45 of 47	1		ENSP00000489778.1
CACNA1A	ENST00000636012.1	c.6434G>T	p.Arg2145Leu	missense_variant	Exon 44 of 46	5		ENSP00000490223.1
CACNA1A	ENST00000637736.1	c.6329G>T	p.Arg2110Leu	missense_variant	Exon 44 of 46	5		ENSP00000489861.1
CACNA1A	ENST00000636389.1	c.6470G>T	p.Arg2157Leu	missense_variant	Exon 45 of 47	5		ENSP00000489992.1
CACNA1A	ENST00000637432.1	c.6485G>T	p.Arg2162Leu	missense_variant	Exon 46 of 48	5		ENSP00000490617.1
CACNA1A	ENST00000636549.1	c.6476G>T	p.Arg2159Leu	missense_variant	Exon 46 of 48	5		ENSP00000490578.1
CACNA1A	ENST00000637927.1	c.6473G>T	p.Arg2158Leu	missense_variant	Exon 45 of 47	5		ENSP00000489715.1
CACNA1A	ENST00000635895.1	c.6470G>T	p.Arg2157Leu	missense_variant	Exon 45 of 47	5		ENSP00000490323.1
CACNA1A	ENST00000638009.2	c.6470G>T	p.Arg2157Leu	missense_variant	Exon 45 of 47	1		ENSP00000489913.1
CACNA1A	ENST00000637276.1	c.6434G>T	p.Arg2145Leu	missense_variant	Exon 44 of 46	5		ENSP00000489777.1
CACNA1A	ENST00000636768.1	n.*733G>T		non_coding_transcript_exon_variant	Exon 9 of 10	5		ENSP00000490190.2
CACNA1A	ENST00000636768.1	n.*733G>T		3_prime_UTR_variant	Exon 9 of 10	5		ENSP00000490190.2

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152160 Hom.: 0 Cov.: 33

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

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1236324 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 596850

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152160 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 74328

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: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.50
BayesDel_addAF	Uncertain	0.055	T
BayesDel_noAF	Benign	-0.16
CADD	Benign	22
DANN	Benign	0.97
DEOGEN2	Pathogenic	0.80	.;D;T;.;.;.;.;.;T;.;.;T;.;.;.;T;.;.
Eigen	Benign	0.018
Eigen_PC	Benign	-0.099
FATHMM_MKL	Uncertain	0.83	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	0.46	D
MetaRNN	Uncertain	0.64	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	-0.24	T
MutationAssessor	Uncertain	2.4	.;.;.;.;M;.;.;.;.;.;.;.;.;.;.;.;.;.
PrimateAI	Pathogenic	0.84	D
PROVEAN	Pathogenic	-5.0	.;D;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.
REVEL	Uncertain	0.35
Sift	Uncertain	0.021	.;D;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.
Sift4G	Uncertain	0.053	T;T;.;.;.;D;.;.;.;.;.;.;.;.;.;.;.;.
Vest4		0.46
MutPred		0.33		.;.;Loss of MoRF binding (P = 0.0849);Loss of MoRF binding (P = 0.0849);Loss of MoRF binding (P = 0.0849);.;.;Loss of MoRF binding (P = 0.0849);.;.;.;.;Loss of MoRF binding (P = 0.0849);.;.;.;.;.;
MVP		0.86
MPC		0.34
ClinPred		0.99	D
GERP RS		3.1
Varity_R		0.54
gMVP		0.41

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: rs755749925; hg19: chr19-13320185;