rs16059

chr19-13207403-G-Achr19-13207403-G-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_001127222.2(CACNA1A):c.7431C>T(p.Tyr2477=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00841 in 1,535,954 control chromosomes in the GnomAD database, including 114 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0074 (11 hom., cov: 31)
  • Exomes 𝑓: 0.0085 (103 hom.)
• Consequence: CACNA1A NM_001127222.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.150

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.65).
• BP6: Variant 19-13207403-G-A is Benign according to our data. Variant chr19-13207403-G-A is described in ClinVar as [Benign]. Clinvar id is 257513.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-13207403-G-A is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=0.15 with no splicing effect.
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00737 (1118/151678) while in subpopulation AMR AF= 0.0202 (308/15244). AF 95% confidence interval is 0.0183. There are 11 homozygotes in gnomad4. There are 580 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High AC in GnomAd at 1113 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CACNA1A	NM_001127222.2	c.7431C>T	p.Tyr2477=	synonymous_variant	47/47	ENST00000360228.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CACNA1A	ENST00000360228.11	c.7431C>T	p.Tyr2477=	synonymous_variant	47/47	1	NM_001127222.2

Frequencies

GnomAD3 genomes AF: 0.00734 AC: 1113 AN: 151570 Hom.: 10 Cov.: 31

Gnomad AFR AF: 0.00182

Gnomad AMI AF: 0.0399

Gnomad AMR AF: 0.0201

Gnomad ASJ AF: 0.000289

Gnomad EAS AF: 0.00934

Gnomad SAS AF: 0.00994

Gnomad FIN AF: 0.00619

Gnomad MID AF: 0.00318

Gnomad NFE AF: 0.00757

Gnomad OTH AF: 0.00961

GnomAD3 exomes AF: 0.0126 AC: 1749 AN: 139132 Hom.: 28 AF XY: 0.0116 AC XY: 892 AN XY: 77118

Gnomad AFR exome AF: 0.00133

Gnomad AMR exome AF: 0.0327

Gnomad ASJ exome AF: 0.000122

Gnomad EAS exome AF: 0.0144

Gnomad SAS exome AF: 0.0108

Gnomad FIN exome AF: 0.00760

Gnomad NFE exome AF: 0.00749

Gnomad OTH exome AF: 0.0118

GnomAD4 exome AF: 0.00852 AC: 11793 AN: 1384276 Hom.: 103 Cov.: 30 AF XY: 0.00864 AC XY: 5916 AN XY: 685000

Gnomad4 AFR exome AF: 0.00136

Gnomad4 AMR exome AF: 0.0312

Gnomad4 ASJ exome AF: 0.000323

Gnomad4 EAS exome AF: 0.0101

Gnomad4 SAS exome AF: 0.0104

Gnomad4 FIN exome AF: 0.00853

Gnomad4 NFE exome AF: 0.00801

Gnomad4 OTH exome AF: 0.00805

GnomAD4 genome AF: 0.00737 AC: 1118 AN: 151678 Hom.: 11 Cov.: 31 AF XY: 0.00782 AC XY: 580 AN XY: 74164

Gnomad4 AFR AF: 0.00179

Gnomad4 AMR AF: 0.0202

Gnomad4 ASJ AF: 0.000289

Gnomad4 EAS AF: 0.00937

Gnomad4 SAS AF: 0.00974

Gnomad4 FIN AF: 0.00619

Gnomad4 NFE AF: 0.00757

Gnomad4 OTH AF: 0.0119

Alfa AF: 0.00448 Hom.: 1

Bravo AF: 0.00870

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 14, 2016	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Nov 04, 2019	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

not provided Benign:2

Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.65
Cadd	Benign	6.4
Dann	Benign	0.97

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: rs16059; hg19: chr19-13318217;