rs201836062

chr19-13224748-C-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 1P and 13B. PP2 BP4_Strong BP6 BS1 BS2

The NM_001127222.2(CACNA1A):c.5650G>A(p.Val1884Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000122 in 1,609,356 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V1884D) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00060 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000072 (1 hom.)
• Consequence: CACNA1A NM_001127222.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:6
• Conservation: PhyloP100: 0.618

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 Benign. Variant got -12 ACMG points.

• PP2: Missense variant where missense usually causes diseases, CACNA1A
• BP4: Computational evidence support a benign effect (MetaRNN=0.017831832).
• BP6: Variant 19-13224748-C-T is Benign according to our data. Variant chr19-13224748-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 384036.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Likely_benign=4, Benign=2}.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.000598 (91/152184) while in subpopulation AFR AF= 0.00205 (85/41506). AF 95% confidence interval is 0.0017. There are 0 homozygotes in gnomad4. There are 36 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High AC in GnomAd at 91 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CACNA1A	NM_001127222.2	c.5650G>A	p.Val1884Ile	missense_variant	38/47	ENST00000360228.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CACNA1A	ENST00000360228.11	c.5650G>A	p.Val1884Ile	missense_variant	38/47	1	NM_001127222.2

Frequencies

GnomAD3 genomes AF: 0.000598 AC: 91 AN: 152066 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00205

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000580

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000480

GnomAD3 exomes AF: 0.000184 AC: 44 AN: 238884 Hom.: 0 AF XY: 0.000154 AC XY: 20 AN XY: 130084

Gnomad AFR exome AF: 0.00146

Gnomad AMR exome AF: 0.000510

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000230

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000484

Gnomad NFE exome AF: 0.00000925

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000721 AC: 105 AN: 1457172 Hom.: 1 Cov.: 31 AF XY: 0.0000649 AC XY: 47 AN XY: 724480

Gnomad4 AFR exome AF: 0.00144

Gnomad4 AMR exome AF: 0.000432

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000253

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000189

Gnomad4 NFE exome AF: 0.0000279

Gnomad4 OTH exome AF: 0.0000831

GnomAD4 genome AF: 0.000598 AC: 91 AN: 152184 Hom.: 0 Cov.: 31 AF XY: 0.000484 AC XY: 36 AN XY: 74394

Gnomad4 AFR AF: 0.00205

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000581

Gnomad4 SAS AF: 0.000208

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.000475

Alfa AF: 0.000162 Hom.: 0

Bravo AF: 0.000691

ESP6500AA AF: 0.00222 AC: 9

ESP6500EA AF: 0.000120 AC: 1

ExAC AF: 0.000215 AC: 26

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:6

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jul 25, 2017	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 03, 2021	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Athena Diagnostics

Apr 05, 2021

- -

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

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 15, 2024

- -

Inborn genetic diseases Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 01, 2017

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. -

CACNA1A-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 08, 2022

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). -

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

Likely benign, criteria provided, single submitter

clinical testing

Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago

Aug 18, 2022

This variant has not been reported in the literature but is present in the Genome Aggregation Database (Highest reported MAF 0.2% (85/41384) (https://gnomad.broadinstitute.org/variant/19-13224748-C-T?dataset=gnomad_r3). This variant is present in ClinVar, with several labs classifying this variant as Likely Benign or Benign (Variation ID:384036). This variant amino acid Isoleucine (Ile) is present in several species; this suggests that this variant may not impact the protein. However, additional computational prediction tools do suggest an impact. In summary, data on this variant suggests that this variant does not cause disease but requires further evidence. Therefore, this variant is classified as likely benign. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_addAF	Benign	-0.40	T
BayesDel_noAF	Benign	-0.38
Cadd	Benign	22
Dann	Benign	0.92
Eigen	Benign	-0.45
Eigen_PC	Benign	-0.32
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Uncertain	0.96	D;D;D;D;D;D;D;D;D;D;.;D;D;D;D;D;D;D;D
M_CAP	Benign	0.0071	T
MetaRNN	Benign	0.018	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.52	T
Sift4G	Benign	0.52	T;T;.;.;.;T;.;.;.;.;.;.;.;.;.;.;.;.;.
Vest4		0.13
MVP		0.57
MPC		1.0
ClinPred		0.029	T
GERP RS		4.3
Varity_R		0.033
gMVP		0.53

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: rs201836062; hg19: chr19-13335562; COSMIC: COSV64203710; COSMIC: COSV64203710;