rs141963371

Positions:

• chr19-13212695-T-C

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 1P and 7B. PP2 BP4_Moderate BP6 BS2

The NM_001127222.2(CACNA1A):​c.5986A>G​(p.Thr1996Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000543 in 1,510,702 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.000046 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000055 (0 hom.)
• Consequence: CACNA1A NM_001127222.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:2
• Conservation: PhyloP100: 1.40

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 -6 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=0.084127486).
• BP6: Variant 19-13212695-T-C is Benign according to our data. Variant chr19-13212695-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 450300.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=3}.
• BS2: High AC in GnomAd4 at 7 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CACNA1A	NM_001127222.2	c.5986A>G	p.Thr1996Ala	missense_variant	41/47	ENST00000360228.11	NP_001120694.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CACNA1A	ENST00000360228.11	c.5986A>G	p.Thr1996Ala	missense_variant	41/47	1	NM_001127222.2	ENSP00000353362.5
CACNA1A	ENST00000638029.1	c.6004A>G	p.Thr2002Ala	missense_variant	42/48	5		ENSP00000489829.1
CACNA1A	ENST00000573710.7	c.5992A>G	p.Thr1998Ala	missense_variant	41/47	5		ENSP00000460092.3
CACNA1A	ENST00000635727.1	c.5989A>G	p.Thr1997Ala	missense_variant	41/47	5		ENSP00000490001.1
CACNA1A	ENST00000637769.1	c.5989A>G	p.Thr1997Ala	missense_variant	41/47	1		ENSP00000489778.1
CACNA1A	ENST00000636012.1	c.5989A>G	p.Thr1997Ala	missense_variant	41/46	5		ENSP00000490223.1
CACNA1A	ENST00000637736.1	c.5848A>G	p.Thr1950Ala	missense_variant	40/46	5		ENSP00000489861.1
CACNA1A	ENST00000636389.1	c.5989A>G	p.Thr1997Ala	missense_variant	41/47	5		ENSP00000489992.1
CACNA1A	ENST00000637432.1	c.6004A>G	p.Thr2002Ala	missense_variant	42/48	5		ENSP00000490617.1
CACNA1A	ENST00000636549.1	c.5995A>G	p.Thr1999Ala	missense_variant	42/48	5		ENSP00000490578.1
CACNA1A	ENST00000637927.1	c.5992A>G	p.Thr1998Ala	missense_variant	41/47	5		ENSP00000489715.1
CACNA1A	ENST00000635895.1	c.5989A>G	p.Thr1997Ala	missense_variant	41/47	5		ENSP00000490323.1
CACNA1A	ENST00000638009.2	c.5989A>G	p.Thr1997Ala	missense_variant	41/47	1		ENSP00000489913.1
CACNA1A	ENST00000637276.1	c.5989A>G	p.Thr1997Ala	missense_variant	41/46	5		ENSP00000489777.1
CACNA1A	ENST00000636768.1	n.*288A>G		non_coding_transcript_exon_variant	6/10	5		ENSP00000490190.2
CACNA1A	ENST00000636768.1	n.*288A>G		3_prime_UTR_variant	6/10	5		ENSP00000490190.2

Frequencies

GnomAD3 genomes AF: 0.0000461 AC: 7 AN: 151990 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000416

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000489 AC: 8 AN: 163620 Hom.: 0 AF XY: 0.0000462 AC XY: 4 AN XY: 86494

Gnomad AFR exome AF: 0.0000762

Gnomad AMR exome AF: 0.0000498

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000756

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000623

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000552 AC: 75 AN: 1358594 Hom.: 0 Cov.: 33 AF XY: 0.0000572 AC XY: 38 AN XY: 664366

Gnomad4 AFR exome AF: 0.0000663

Gnomad4 AMR exome AF: 0.0000696

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000723

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000593

Gnomad4 OTH exome AF: 0.0000358

GnomAD4 genome AF: 0.0000460 AC: 7 AN: 152108 Hom.: 0 Cov.: 32 AF XY: 0.0000672 AC XY: 5 AN XY: 74358

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000416

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000529

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000361 AC: 3

ExAC AF: 0.0000686 AC: 8

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:2 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jan 29, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 16, 2020	- -
Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2023	CACNA1A: PP2 -

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 02, 2021

The c.5989A>G (p.T1997A) alteration is located in exon 41 (coding exon 41) of the CACNA1A gene. This alteration results from a A to G substitution at nucleotide position 5989, causing the threonine (T) at amino acid position 1997 to be replaced by an alanine (A). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

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 25, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.074
BayesDel_addAF	Benign	-0.062	T
BayesDel_noAF	Benign	-0.14
CADD	Benign	21
DANN	Benign	0.53
DEOGEN2	Benign	0.019	.;.;T;.;.;.;.;.;T;.;.;T;.;.;.;T;.;.
Eigen	Benign	-0.75
Eigen_PC	Benign	-0.72
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Benign	0.77	T;T;T;T;T;T;T;T;T;T;.;T;T;T;T;T;T;T
M_CAP	Uncertain	0.11	D
MetaRNN	Benign	0.084	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Uncertain	-0.085	T
MutationAssessor	Benign	1.9	.;.;.;.;L;.;.;.;.;.;.;.;.;.;L;.;.;.
PrimateAI	Uncertain	0.59	T
PROVEAN	Benign	-2.0	.;N;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.
REVEL	Benign	0.25
Sift	Benign	0.63	.;T;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.
Sift4G	Benign	0.57	T;T;.;.;.;T;.;.;.;.;.;.;.;.;.;.;.;.
Vest4		0.31
MVP		0.86
MPC		0.47
ClinPred		0.029	T
GERP RS		3.3
Varity_R		0.11
gMVP		0.13

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: rs141963371; hg19: chr19-13323509; COSMIC: COSV64198896; COSMIC: COSV64198896;