rs563345694

Variant names:

• chr19-13212448-G-A
• rs563345694
• NM_001127222.2:c.6125C>T

Your query was ambiguous. Multiple possible variants found:

• chr19-13212448-G-A
• chr19-13212448-G-C

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 1P and 5B. PP2 BP6 BS2

The NM_001127222.2(CACNA1A):​c.6125C>T​(p.Thr2042Met) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000639 in 1,610,832 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. T2042T) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.000053 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000065 (0 hom.)
• Consequence: CACNA1A NM_001127222.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5 B:3
• Conservation: PhyloP100: 7.59

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 Likely_benign. Variant got -4 ACMG points.

• 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.
• BP6: Variant 19-13212448-G-A is Benign according to our data. Variant chr19-13212448-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 386521.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Uncertain_significance=5}.
• BS2: High AC in GnomAd4 at 8 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1A	NM_001127222.2	c.6125C>T	p.Thr2042Met	missense_variant	Exon 42 of 47	ENST00000360228.11	NP_001120694.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CACNA1A	ENST00000360228.11	c.6125C>T	p.Thr2042Met	missense_variant	Exon 42 of 47	1	NM_001127222.2	ENSP00000353362.5
CACNA1A	ENST00000638029.1	c.6143C>T	p.Thr2048Met	missense_variant	Exon 43 of 48	5		ENSP00000489829.1
CACNA1A	ENST00000573710.7	c.6131C>T	p.Thr2044Met	missense_variant	Exon 42 of 47	5		ENSP00000460092.3
CACNA1A	ENST00000635727.1	c.6128C>T	p.Thr2043Met	missense_variant	Exon 42 of 47	5		ENSP00000490001.1
CACNA1A	ENST00000637769.1	c.6128C>T	p.Thr2043Met	missense_variant	Exon 42 of 47	1		ENSP00000489778.1
CACNA1A	ENST00000636012.1	c.6128C>T	p.Thr2043Met	missense_variant	Exon 42 of 46	5		ENSP00000490223.1
CACNA1A	ENST00000637736.1	c.5987C>T	p.Thr1996Met	missense_variant	Exon 41 of 46	5		ENSP00000489861.1
CACNA1A	ENST00000636389.1	c.6128C>T	p.Thr2043Met	missense_variant	Exon 42 of 47	5		ENSP00000489992.1
CACNA1A	ENST00000637432.1	c.6143C>T	p.Thr2048Met	missense_variant	Exon 43 of 48	5		ENSP00000490617.1
CACNA1A	ENST00000636549.1	c.6134C>T	p.Thr2045Met	missense_variant	Exon 43 of 48	5		ENSP00000490578.1
CACNA1A	ENST00000637927.1	c.6131C>T	p.Thr2044Met	missense_variant	Exon 42 of 47	5		ENSP00000489715.1
CACNA1A	ENST00000635895.1	c.6128C>T	p.Thr2043Met	missense_variant	Exon 42 of 47	5		ENSP00000490323.1
CACNA1A	ENST00000638009.2	c.6128C>T	p.Thr2043Met	missense_variant	Exon 42 of 47	1		ENSP00000489913.1
CACNA1A	ENST00000637276.1	c.6128C>T	p.Thr2043Met	missense_variant	Exon 42 of 46	5		ENSP00000489777.1
CACNA1A	ENST00000636768.1	n.*427C>T		non_coding_transcript_exon_variant	Exon 7 of 10	5		ENSP00000490190.2
CACNA1A	ENST00000636768.1	n.*427C>T		3_prime_UTR_variant	Exon 7 of 10	5		ENSP00000490190.2

Frequencies

GnomAD3 genomes AF: 0.0000526 AC: 8 AN: 152144 Hom.: 0 Cov.: 32

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: 0.0000882

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.0000374 AC: 9 AN: 240506 Hom.: 0 AF XY: 0.0000460 AC XY: 6 AN XY: 130564

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000597

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: 0.0000548

Gnomad OTH exome AF: 0.000171

GnomAD4 exome AF: 0.0000651 AC: 95 AN: 1458688 Hom.: 0 Cov.: 34 AF XY: 0.0000607 AC XY: 44 AN XY: 725350

Gnomad4 AFR exome AF: 0.0000598

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: 0.0000188

Gnomad4 NFE exome AF: 0.0000747

Gnomad4 OTH exome AF: 0.0000332

GnomAD4 genome AF: 0.0000526 AC: 8 AN: 152144 Hom.: 0 Cov.: 32 AF XY: 0.0000538 AC XY: 4 AN XY: 74308

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: 0.0000882

Gnomad4 OTH AF: 0.000478

Alfa AF: 0.0000847 Hom.: 0

Bravo AF: 0.0000416

ExAC AF: 0.0000165 AC: 2

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:5 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:3 Benign:1

Jun 01, 2018

CeGaT Center for Human Genetics Tuebingen

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 27, 2018

Athena Diagnostics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 19, 2018

Center for Personalized Medicine, Children's Hospital Los Angeles

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 18, 2021

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 30755392) -

CACNA1A-related disorder Uncertain:1

Dec 28, 2022

PreventionGenetics, part of Exact Sciences

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The CACNA1A c.6125C>T variant is predicted to result in the amino acid substitution p.Thr2042Met. This variant was reported in an individual with cerebral white matter abnormalities, cerebral venous thrombosis, myelitis, immunodeficiency, and spasticity (referred to as c.6128C>T, p.Thr2043Met in Supplemental Table 2, Ji et al. 2019. PubMed ID: 30755392). This variant is reported in 0.0058% of alleles in individuals of Latino descent in gnomAD (http://gnomad.broadinstitute.org/variant/19-13323262-G-A). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

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

Oct 31, 2018

Fulgent Genetics, Fulgent Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Episodic ataxia type 2;C4310716:Developmental and epileptic encephalopathy, 42 Benign:1

Jan 08, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Inborn genetic diseases Benign:1

Jan 17, 2019

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Pathogenic	0.21	D
BayesDel_noAF	Pathogenic	0.24
CADD	Pathogenic	27
DANN	Uncertain	0.99
DEOGEN2	Benign	0.032	.;.;T;.;.;.;.;.;T;.;.;T;.;.;.;T;.;.
Eigen	Uncertain	0.35
Eigen_PC	Uncertain	0.31
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Pathogenic	0.99	D;D;D;D;D;D;D;D;D;D;.;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.34	D
MetaRNN	Uncertain	0.68	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.79	D
MutationAssessor	Uncertain	2.4	.;.;.;.;M;.;.;.;.;.;.;.;.;.;M;.;.;.
PrimateAI	Pathogenic	0.79	T
PROVEAN	Uncertain	-3.3	.;D;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.
REVEL	Pathogenic	0.68
Sift	Uncertain	0.010	.;D;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.
Sift4G	Benign	0.11	T;T;.;.;.;T;.;.;.;.;.;.;.;.;.;.;.;.
Vest4		0.51
MutPred		0.34		.;.;Loss of methylation at K2042 (P = 0.0508);Loss of methylation at K2042 (P = 0.0508);Loss of methylation at K2042 (P = 0.0508);.;.;Loss of methylation at K2042 (P = 0.0508);.;.;.;Loss of methylation at K2042 (P = 0.0508);Loss of methylation at K2042 (P = 0.0508);.;Loss of methylation at K2042 (P = 0.0508);.;.;.;
MVP		0.93
MPC		0.88
ClinPred		0.61	D
GERP RS		3.6
Varity_R		0.10
gMVP		0.34

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: rs563345694; hg19: chr19-13323262;