rs201200430

Positions:

• chr19-13261479-G-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6 BP7 BS1 BS2

The NM_001127222.2(CACNA1A):​c.4221C>T​(p.Asp1407Asp) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000188 in 1,582,532 control chromosomes in the GnomAD database, including 1 homozygotes. 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 0.00033 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00017 (0 hom.)
• Consequence: CACNA1A NM_001127222.2 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:6
• Conservation: PhyloP100: -0.568

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.49).
• BP6: Variant 19-13261479-G-A is Benign according to our data. Variant chr19-13261479-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 283176.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Likely_benign=2, Benign=3}.
• BP7: Synonymous conserved (PhyloP=-0.568 with no splicing effect.
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.000328 (50/152284) while in subpopulation AMR AF= 0.0017 (26/15300). AF 95% confidence interval is 0.00119. There are 1 homozygotes in gnomad4. There are 22 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 50 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CACNA1A	NM_001127222.2	c.4221C>T	p.Asp1407Asp	synonymous_variant	26/47	ENST00000360228.11	NP_001120694.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CACNA1A	ENST00000360228.11	c.4221C>T	p.Asp1407Asp	synonymous_variant	26/47	1	NM_001127222.2	ENSP00000353362.5
CACNA1A	ENST00000638029.1	c.4233C>T	p.Asp1411Asp	synonymous_variant	26/48	5		ENSP00000489829.1
CACNA1A	ENST00000573710.7	c.4227C>T	p.Asp1409Asp	synonymous_variant	26/47	5		ENSP00000460092.3
CACNA1A	ENST00000635727.1	c.4224C>T	p.Asp1408Asp	synonymous_variant	26/47	5		ENSP00000490001.1
CACNA1A	ENST00000637769.1	c.4224C>T	p.Asp1408Asp	synonymous_variant	26/47	1		ENSP00000489778.1
CACNA1A	ENST00000636012.1	c.4224C>T	p.Asp1408Asp	synonymous_variant	26/46	5		ENSP00000490223.1
CACNA1A	ENST00000637736.1	c.4083C>T	p.Asp1361Asp	synonymous_variant	25/46	5		ENSP00000489861.1
CACNA1A	ENST00000636389.1	c.4224C>T	p.Asp1408Asp	synonymous_variant	26/47	5		ENSP00000489992.1
CACNA1A	ENST00000637432.1	c.4233C>T	p.Asp1411Asp	synonymous_variant	26/48	5		ENSP00000490617.1
CACNA1A	ENST00000636549.1	c.4224C>T	p.Asp1408Asp	synonymous_variant	26/48	5		ENSP00000490578.1
CACNA1A	ENST00000637927.1	c.4227C>T	p.Asp1409Asp	synonymous_variant	26/47	5		ENSP00000489715.1
CACNA1A	ENST00000635895.1	c.4224C>T	p.Asp1408Asp	synonymous_variant	26/47	5		ENSP00000490323.1
CACNA1A	ENST00000638009.2	c.4224C>T	p.Asp1408Asp	synonymous_variant	26/47	1		ENSP00000489913.1
CACNA1A	ENST00000637276.1	c.4224C>T	p.Asp1408Asp	synonymous_variant	26/46	5		ENSP00000489777.1

Frequencies

GnomAD3 genomes AF: 0.000335 AC: 51 AN: 152166 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000362

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00170

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000943

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000882

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000462 AC: 93 AN: 201176 Hom.: 0 AF XY: 0.000391 AC XY: 42 AN XY: 107492

Gnomad AFR exome AF: 0.000170

Gnomad AMR exome AF: 0.00229

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000690

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.000106

Gnomad NFE exome AF: 0.000147

Gnomad OTH exome AF: 0.00210

GnomAD4 exome AF: 0.000173 AC: 247 AN: 1430248 Hom.: 0 Cov.: 31 AF XY: 0.000167 AC XY: 118 AN XY: 708282

Gnomad4 AFR exome AF: 0.000334

Gnomad4 AMR exome AF: 0.00232

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000520

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000776

Gnomad4 NFE exome AF: 0.000113

Gnomad4 OTH exome AF: 0.000269

GnomAD4 genome AF: 0.000328 AC: 50 AN: 152284 Hom.: 1 Cov.: 32 AF XY: 0.000295 AC XY: 22 AN XY: 74454

Gnomad4 AFR AF: 0.000337

Gnomad4 AMR AF: 0.00170

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000386

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0000943

Gnomad4 NFE AF: 0.0000882

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000196 Hom.: 0

Bravo AF: 0.000465

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:2

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2024	CACNA1A: BP4, BP7, BS1 -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Oct 24, 2017	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 22, 2019	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Athena Diagnostics

Dec 29, 2016

- -

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

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 29, 2024

- -

Inborn genetic diseases Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 07, 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, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 20, 2019

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
BayesDel_noAF	Benign	-0.49
CADD	Benign	1.6
DANN	Benign	0.91

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: rs201200430; hg19: chr19-13372293;