19-13209496-G-C

Position:

• chr19-13209496-G-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001127222.2(CACNA1A):​c.6342C>G​(p.Thr2114Thr) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00402 in 1,309,830 control chromosomes in the GnomAD database, including 145 homozygotes. In-silico tool predicts a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.019 (85 hom., cov: 33)
  • Exomes 𝑓: 0.0020 (60 hom.)
• Consequence: CACNA1A NM_001127222.2 splice_region, synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 1.79

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 Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.53).
• BP6: Variant 19-13209496-G-C is Benign according to our data. Variant chr19-13209496-G-C is described in ClinVar as [Likely_benign]. Clinvar id is 128557.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-13209496-G-C is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=1.79 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0647 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CACNA1A	NM_001127222.2	c.6342C>G	p.Thr2114Thr	splice_region_variant, synonymous_variant	45/47	ENST00000360228.11	NP_001120694.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CACNA1A	ENST00000360228.11	c.6342C>G	p.Thr2114Thr	splice_region_variant, synonymous_variant	45/47	1	NM_001127222.2	ENSP00000353362.5
CACNA1A	ENST00000638029.1	c.6360C>G	p.Thr2120Thr	splice_region_variant, synonymous_variant	46/48	5		ENSP00000489829.1
CACNA1A	ENST00000573710.7	c.6348C>G	p.Thr2116Thr	splice_region_variant, synonymous_variant	45/47	5		ENSP00000460092.3
CACNA1A	ENST00000635727.1	c.6345C>G	p.Thr2115Thr	splice_region_variant, synonymous_variant	45/47	5		ENSP00000490001.1
CACNA1A	ENST00000637769.1	c.6345C>G	p.Thr2115Thr	splice_region_variant, synonymous_variant	45/47	1		ENSP00000489778.1
CACNA1A	ENST00000636012.1	c.6309C>G	p.Thr2103Thr	splice_region_variant, synonymous_variant	44/46	5		ENSP00000490223.1
CACNA1A	ENST00000637736.1	c.6204C>G	p.Thr2068Thr	splice_region_variant, synonymous_variant	44/46	5		ENSP00000489861.1
CACNA1A	ENST00000636389.1	c.6345C>G	p.Thr2115Thr	splice_region_variant, synonymous_variant	45/47	5		ENSP00000489992.1
CACNA1A	ENST00000637432.1	c.6360C>G	p.Thr2120Thr	splice_region_variant, synonymous_variant	46/48	5		ENSP00000490617.1
CACNA1A	ENST00000636549.1	c.6351C>G	p.Thr2117Thr	splice_region_variant, synonymous_variant	46/48	5		ENSP00000490578.1
CACNA1A	ENST00000637927.1	c.6348C>G	p.Thr2116Thr	splice_region_variant, synonymous_variant	45/47	5		ENSP00000489715.1
CACNA1A	ENST00000635895.1	c.6345C>G	p.Thr2115Thr	splice_region_variant, synonymous_variant	45/47	5		ENSP00000490323.1
CACNA1A	ENST00000638009.2	c.6345C>G	p.Thr2115Thr	splice_region_variant, synonymous_variant	45/47	1		ENSP00000489913.1
CACNA1A	ENST00000637276.1	c.6309C>G	p.Thr2103Thr	splice_region_variant, synonymous_variant	44/46	5		ENSP00000489777.1
CACNA1A	ENST00000636768.1	n.*608C>G		splice_region_variant, non_coding_transcript_exon_variant	9/10	5		ENSP00000490190.2
CACNA1A	ENST00000636768.1	n.*608C>G		3_prime_UTR_variant	9/10	5		ENSP00000490190.2

Frequencies

GnomAD3 genomes AF: 0.0193 AC: 2933 AN: 152174 Hom.: 84 Cov.: 33

Gnomad AFR AF: 0.0668

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00713

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.000382

Gnomad OTH AF: 0.0124

GnomAD3 exomes AF: 0.00467 AC: 234 AN: 50124 Hom.: 6 AF XY: 0.00354 AC XY: 93 AN XY: 26298

Gnomad AFR exome AF: 0.0586

Gnomad AMR exome AF: 0.00386

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: 0.000532

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00200 AC: 2316 AN: 1157538 Hom.: 60 Cov.: 32 AF XY: 0.00178 AC XY: 984 AN XY: 552728

Gnomad4 AFR exome AF: 0.0753

Gnomad4 AMR exome AF: 0.00500

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000213

Gnomad4 OTH exome AF: 0.00426

GnomAD4 genome AF: 0.0193 AC: 2943 AN: 152292 Hom.: 85 Cov.: 33 AF XY: 0.0192 AC XY: 1427 AN XY: 74470

Gnomad4 AFR AF: 0.0668

Gnomad4 AMR AF: 0.00713

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000382

Gnomad4 OTH AF: 0.0128

Alfa AF: 0.0165 Hom.: 7

Bravo AF: 0.0229

Asia WGS AF: 0.00549 AC: 19 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	May 18, 2016	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 13, 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. -
Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Dec 28, 2018	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

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

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

Inborn genetic diseases Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 27, 2016

This alteration is classified as 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. -

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

Fulgent Genetics, Fulgent Genetics

Oct 08, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.53
CADD	Benign	8.7
DANN	Benign	0.82

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: rs16049; hg19: chr19-13320310; COSMIC: COSV100803036; COSMIC: COSV100803036;