19-13212693-C-T

Position:

• chr19-13212693-C-T

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.5988G>A​(p.Thr1996Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000358 in 1,508,718 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000039 (0 hom.)
• Consequence: CACNA1A NM_001127222.2 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -3.78

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=-0.58).
• BP6: Variant 19-13212693-C-T is Benign according to our data. Variant chr19-13212693-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 446935.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-3.78 with no splicing effect.
• BS1: Variant frequency is greater than expected in population eas. gnomad4_exome allele frequency = 0.0000391 (53/1356676) while in subpopulation EAS AF= 0.000834 (32/38380). AF 95% confidence interval is 0.000606. There are 0 homozygotes in gnomad4_exome. There are 18 alleles in male gnomad4_exome subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High AC in GnomAdExome4 at 53 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CACNA1A	NM_001127222.2	c.5988G>A	p.Thr1996Thr	synonymous_variant	41/47	ENST00000360228.11	NP_001120694.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CACNA1A	ENST00000360228.11	c.5988G>A	p.Thr1996Thr	synonymous_variant	41/47	1	NM_001127222.2	ENSP00000353362.5
CACNA1A	ENST00000638029.1	c.6006G>A	p.Thr2002Thr	synonymous_variant	42/48	5		ENSP00000489829.1
CACNA1A	ENST00000573710.7	c.5994G>A	p.Thr1998Thr	synonymous_variant	41/47	5		ENSP00000460092.3
CACNA1A	ENST00000635727.1	c.5991G>A	p.Thr1997Thr	synonymous_variant	41/47	5		ENSP00000490001.1
CACNA1A	ENST00000637769.1	c.5991G>A	p.Thr1997Thr	synonymous_variant	41/47	1		ENSP00000489778.1
CACNA1A	ENST00000636012.1	c.5991G>A	p.Thr1997Thr	synonymous_variant	41/46	5		ENSP00000490223.1
CACNA1A	ENST00000637736.1	c.5850G>A	p.Thr1950Thr	synonymous_variant	40/46	5		ENSP00000489861.1
CACNA1A	ENST00000636389.1	c.5991G>A	p.Thr1997Thr	synonymous_variant	41/47	5		ENSP00000489992.1
CACNA1A	ENST00000637432.1	c.6006G>A	p.Thr2002Thr	synonymous_variant	42/48	5		ENSP00000490617.1
CACNA1A	ENST00000636549.1	c.5997G>A	p.Thr1999Thr	synonymous_variant	42/48	5		ENSP00000490578.1
CACNA1A	ENST00000637927.1	c.5994G>A	p.Thr1998Thr	synonymous_variant	41/47	5		ENSP00000489715.1
CACNA1A	ENST00000635895.1	c.5991G>A	p.Thr1997Thr	synonymous_variant	41/47	5		ENSP00000490323.1
CACNA1A	ENST00000638009.2	c.5991G>A	p.Thr1997Thr	synonymous_variant	41/47	1		ENSP00000489913.1
CACNA1A	ENST00000637276.1	c.5991G>A	p.Thr1997Thr	synonymous_variant	41/46	5		ENSP00000489777.1
CACNA1A	ENST00000636768.1	n.*290G>A		non_coding_transcript_exon_variant	6/10	5		ENSP00000490190.2
CACNA1A	ENST00000636768.1	n.*290G>A		3_prime_UTR_variant	6/10	5		ENSP00000490190.2

Frequencies

GnomAD3 genomes AF: 0.00000658 AC: 1 AN: 151924 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000740 AC: 12 AN: 162232 Hom.: 0 AF XY: 0.0000816 AC XY: 7 AN XY: 85752

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000748

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000126

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000391 AC: 53 AN: 1356676 Hom.: 0 Cov.: 33 AF XY: 0.0000271 AC XY: 18 AN XY: 663320

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000834

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000179

Gnomad4 OTH exome AF: 0.0000359

GnomAD4 genome AF: 0.00000658 AC: 1 AN: 152042 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74318

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000194

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000340

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Athena Diagnostics

Jun 21, 2017

- -

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

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Nov 27, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.58
CADD	Benign	1.8
DANN	Benign	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: rs17846933; hg19: chr19-13323507;