19-13286521-T-G

Position:

• chr19-13286521-T-G

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 1P and 6B. PP2 BP4_Moderate BS2

The NM_001127222.2(CACNA1A):​c.3535A>C​(p.Asn1179His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000645 in 1,007,356 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.0000072 (0 hom., cov: 29)
  • Exomes 𝑓: 0.000074 (0 hom.)
• Consequence: CACNA1A NM_001127222.2 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 1.05

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 Likely_benign. Variant got -5 ACMG points.

• 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=0.20711431).
• BS2: High AC in GnomAdExome4 at 64 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CACNA1A	NM_001127222.2	c.3535A>C	p.Asn1179His	missense_variant	20/47	ENST00000360228.11	NP_001120694.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CACNA1A	ENST00000360228.11	c.3535A>C	p.Asn1179His	missense_variant	20/47	1	NM_001127222.2	ENSP00000353362.5
CACNA1A	ENST00000638029.1	c.3547A>C	p.Asn1183His	missense_variant	20/48	5		ENSP00000489829.1
CACNA1A	ENST00000573710.7	c.3541A>C	p.Asn1181His	missense_variant	20/47	5		ENSP00000460092.3
CACNA1A	ENST00000635727.1	c.3538A>C	p.Asn1180His	missense_variant	20/47	5		ENSP00000490001.1
CACNA1A	ENST00000637769.1	c.3538A>C	p.Asn1180His	missense_variant	20/47	1		ENSP00000489778.1
CACNA1A	ENST00000636012.1	c.3538A>C	p.Asn1180His	missense_variant	20/46	5		ENSP00000490223.1
CACNA1A	ENST00000637736.1	c.3397A>C	p.Asn1133His	missense_variant	19/46	5		ENSP00000489861.1
CACNA1A	ENST00000636389.1	c.3538A>C	p.Asn1180His	missense_variant	20/47	5		ENSP00000489992.1
CACNA1A	ENST00000637432.1	c.3547A>C	p.Asn1183His	missense_variant	20/48	5		ENSP00000490617.1
CACNA1A	ENST00000636549.1	c.3538A>C	p.Asn1180His	missense_variant	20/48	5		ENSP00000490578.1
CACNA1A	ENST00000637927.1	c.3541A>C	p.Asn1181His	missense_variant	20/47	5		ENSP00000489715.1
CACNA1A	ENST00000635895.1	c.3538A>C	p.Asn1180His	missense_variant	20/47	5		ENSP00000490323.1
CACNA1A	ENST00000638009.2	c.3538A>C	p.Asn1180His	missense_variant	20/47	1		ENSP00000489913.1
CACNA1A	ENST00000637276.1	c.3538A>C	p.Asn1180His	missense_variant	20/46	5		ENSP00000489777.1

Frequencies

GnomAD3 genomes AF: 0.00000718 AC: 1 AN: 139224 Hom.: 0 Cov.: 29

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000238

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 AF: 0.0000737 AC: 64 AN: 867994 Hom.: 0 Cov.: 19 AF XY: 0.0000620 AC XY: 27 AN XY: 435832

Gnomad4 AFR exome AF: 0.0000513

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.0000755

Gnomad4 EAS exome AF: 0.0000421

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000906

Gnomad4 OTH exome AF: 0.0000562

GnomAD4 genome AF: 0.00000718 AC: 1 AN: 139362 Hom.: 0 Cov.: 29 AF XY: 0.00 AC XY: 0 AN XY: 67502

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000239

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jun 11, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jul 23, 2024	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.50
CADD	Uncertain	23
DANN	Benign	0.83
DEOGEN2	Benign	0.032	.;.;T;.;.;.;.;.;.;T;.;.;.;T;.
Eigen	Benign	-0.29
Eigen_PC	Benign	-0.11
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.76	T;T;T;T;T;T;T;T;.;T;T;T;T;T;T
M_CAP	Benign	0.029	D
MetaRNN	Benign	0.21	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.7	.;.;.;.;L;.;.;.;.;.;.;.;L;.;.
PrimateAI	Uncertain	0.59	T
PROVEAN	Uncertain	-2.6	.;D;.;.;.;.;.;.;.;.;.;.;.;.;.
REVEL	Benign	0.078
Sift	Benign	0.072	.;T;.;.;.;.;.;.;.;.;.;.;.;.;.
Sift4G	Benign	0.14	T;T;.;.;.;.;.;.;.;.;.;.;.;.;.
Vest4		0.16
MutPred		0.16		.;.;Loss of stability (P = 0.0856);Loss of stability (P = 0.0856);Loss of stability (P = 0.0856);.;Loss of stability (P = 0.0856);.;.;Loss of stability (P = 0.0856);Loss of stability (P = 0.0856);.;Loss of stability (P = 0.0856);.;Loss of stability (P = 0.0856);
MVP		0.48
MPC		0.090
ClinPred		0.82	D
GERP RS		4.3
Varity_R		0.21
gMVP		0.43

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: rs964526144; hg19: chr19-13397335;