rs375354077

Positions:

• chr19-13209333-G-A
• chr19-13209333-G-C

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 1P and 11B. PP2 BP4_Moderate BP6 BS1 BS2

The NM_001127222.2(CACNA1A):​c.6505C>T​(p.Arg2169Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000402 in 1,393,218 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 Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00016 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000026 (0 hom.)
• Consequence: CACNA1A NM_001127222.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4 B:3
• Conservation: PhyloP100: 3.11

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 Benign. Variant got -10 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=0.087599635).
• BP6: Variant 19-13209333-G-A is Benign according to our data. Variant chr19-13209333-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 421988.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=4}.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.000158 (24/152164) while in subpopulation AFR AF= 0.000483 (20/41444). AF 95% confidence interval is 0.00032. There are 0 homozygotes in gnomad4. There are 12 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 24 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CACNA1A	NM_001127222.2	c.6505C>T	p.Arg2169Cys	missense_variant	45/47	ENST00000360228.11	NP_001120694.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CACNA1A	ENST00000360228.11	c.6505C>T	p.Arg2169Cys	missense_variant	45/47	1	NM_001127222.2	ENSP00000353362.5
CACNA1A	ENST00000638029.1	c.6523C>T	p.Arg2175Cys	missense_variant	46/48	5		ENSP00000489829.1
CACNA1A	ENST00000573710.7	c.6511C>T	p.Arg2171Cys	missense_variant	45/47	5		ENSP00000460092.3
CACNA1A	ENST00000635727.1	c.6508C>T	p.Arg2170Cys	missense_variant	45/47	5		ENSP00000490001.1
CACNA1A	ENST00000637769.1	c.6508C>T	p.Arg2170Cys	missense_variant	45/47	1		ENSP00000489778.1
CACNA1A	ENST00000636012.1	c.6472C>T	p.Arg2158Cys	missense_variant	44/46	5		ENSP00000490223.1
CACNA1A	ENST00000637736.1	c.6367C>T	p.Arg2123Cys	missense_variant	44/46	5		ENSP00000489861.1
CACNA1A	ENST00000636389.1	c.6508C>T	p.Arg2170Cys	missense_variant	45/47	5		ENSP00000489992.1
CACNA1A	ENST00000637432.1	c.6523C>T	p.Arg2175Cys	missense_variant	46/48	5		ENSP00000490617.1
CACNA1A	ENST00000636549.1	c.6514C>T	p.Arg2172Cys	missense_variant	46/48	5		ENSP00000490578.1
CACNA1A	ENST00000637927.1	c.6511C>T	p.Arg2171Cys	missense_variant	45/47	5		ENSP00000489715.1
CACNA1A	ENST00000635895.1	c.6508C>T	p.Arg2170Cys	missense_variant	45/47	5		ENSP00000490323.1
CACNA1A	ENST00000638009.2	c.6508C>T	p.Arg2170Cys	missense_variant	45/47	1		ENSP00000489913.1
CACNA1A	ENST00000637276.1	c.6472C>T	p.Arg2158Cys	missense_variant	44/46	5		ENSP00000489777.1
CACNA1A	ENST00000636768.1	n.*771C>T		non_coding_transcript_exon_variant	9/10	5		ENSP00000490190.2
CACNA1A	ENST00000636768.1	n.*771C>T		3_prime_UTR_variant	9/10	5		ENSP00000490190.2

Frequencies

GnomAD3 genomes AF: 0.000158 AC: 24 AN: 152164 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

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: 0.000478

GnomAD3 exomes AF: 0.000109 AC: 5 AN: 46082 Hom.: 0 AF XY: 0.0000874 AC XY: 2 AN XY: 22884

Gnomad AFR exome AF: 0.00130

Gnomad AMR exome AF: 0.00

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: 0.0000258 AC: 32 AN: 1241054 Hom.: 0 Cov.: 32 AF XY: 0.0000284 AC XY: 17 AN XY: 598428

Gnomad4 AFR exome AF: 0.000769

Gnomad4 AMR exome AF: 0.0000681

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: 0.00000799

Gnomad4 OTH exome AF: 0.0000591

GnomAD4 genome AF: 0.000158 AC: 24 AN: 152164 Hom.: 0 Cov.: 33 AF XY: 0.000161 AC XY: 12 AN XY: 74324

Gnomad4 AFR AF: 0.000483

Gnomad4 AMR AF: 0.000131

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: 0.000478

Alfa AF: 0.0000639 Hom.: 0

Bravo AF: 0.000196

ESP6500AA AF: 0.000529 AC: 2

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.0000582 AC: 6

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:2 Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Apr 20, 2020	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Mar 22, 2018	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Aug 15, 2016	A variant of uncertain significance has been identified in the CACNA1A gene. The R2170C variant has not beenpublished as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. Although theR2170C was not observed with any significant frequency in approximately 6,000 individuals of European and AfricanAmerican ancestry in the NHLBI Exome Sequencing Project, the data was noted to have reduced depth of sequencingreads and therefore may be unreliable. The R2170C variant is a non-conservative amino acid substitution, which islikely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties.This substitution occurs at a position that is conserved across species and in silico analysis predicts this variant isprobably damaging to the protein structure/function. However, missense variants in nearby residues have not beenreported in the Human Gene Mutation Database in association with CACNA1A-related disorders (Stenson et al.,2014). Therefore, based on the currently available information, it is unclear whether this variant is a pathogenicvariant or a rare benign variant. -

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 25, 2016

The p.R2170C variant (also known as c.6508C>T), located in coding exon 45 of the CACNA1A gene, results from a C to T substitution at nucleotide position 6508. The arginine at codon 2170 is replaced by cysteine, an amino acid with highly dissimilar properties. This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Spinocerebellar ataxia type 6;C1720416:Episodic ataxia type 2;C1832884:Migraine, familial hemiplegic, 1;C4310716:Developmental and epileptic encephalopathy, 42 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 31, 2018

- -

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

Dec 23, 2023

- -

CACNA1A-related disorder Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 22, 2023

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.44
BayesDel_addAF	Benign	-0.060	T
BayesDel_noAF	Uncertain	0.10
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Benign	0.079	.;.;T;.;.;.;.;.;T;.;.;T;.;.;.;T;.;.
Eigen	Uncertain	0.44
Eigen_PC	Uncertain	0.36
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Uncertain	0.97	D;D;D;D;D;D;D;D;D;D;.;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.73	D
MetaRNN	Benign	0.088	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Uncertain	0.63	D
MutationAssessor	Uncertain	2.7	.;.;.;.;M;.;.;.;.;.;.;.;.;.;.;.;.;.
PrimateAI	Pathogenic	0.87	D
PROVEAN	Pathogenic	-4.8	.;D;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.
REVEL	Uncertain	0.63
Sift	Uncertain	0.012	.;D;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.
Sift4G	Benign	0.13	T;T;.;.;.;D;.;.;.;.;.;.;.;.;.;.;.;.
Vest4		0.66
MVP		0.92
MPC		0.97
ClinPred		0.24	T
GERP RS		3.5
Varity_R		0.20
gMVP		0.28

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: rs375354077; hg19: chr19-13320147;