19-13312714-C-T

Variant names:

• chr19-13312714-C-T
• rs375628894
• NM_001127222.2:c.1623G>A

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Moderate BP6 BP7 BS1 BS2

The NM_001127222.2(CACNA1A):​c.1623G>A​(p.Gly541Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000999 in 1,598,026 control chromosomes in the GnomAD database, including 8 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 0.0012 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00098 (7 hom.)
• Consequence: CACNA1A NM_001127222.2 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:6
• Conservation: PhyloP100: 0.392

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.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.3).
• BP6: Variant 19-13312714-C-T is Benign according to our data. Variant chr19-13312714-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 93560.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Benign=3, Uncertain_significance=1}. Variant chr19-13312714-C-T is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=0.392 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00122 (186/152266) while in subpopulation NFE AF= 0.00198 (135/68026). AF 95% confidence interval is 0.00171. There are 1 homozygotes in gnomad4. There are 93 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 186 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1A	NM_001127222.2	c.1623G>A	p.Gly541Gly	synonymous_variant	Exon 12 of 47	ENST00000360228.11	NP_001120694.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CACNA1A	ENST00000360228.11	c.1623G>A	p.Gly541Gly	synonymous_variant	Exon 12 of 47	1	NM_001127222.2	ENSP00000353362.5
CACNA1A	ENST00000638029.1	c.1626G>A	p.Gly542Gly	synonymous_variant	Exon 12 of 48	5		ENSP00000489829.1
CACNA1A	ENST00000573710.7	c.1629G>A	p.Gly543Gly	synonymous_variant	Exon 12 of 47	5		ENSP00000460092.3
CACNA1A	ENST00000635727.1	c.1626G>A	p.Gly542Gly	synonymous_variant	Exon 12 of 47	5		ENSP00000490001.1
CACNA1A	ENST00000637769.1	c.1626G>A	p.Gly542Gly	synonymous_variant	Exon 12 of 47	1		ENSP00000489778.1
CACNA1A	ENST00000636012.1	c.1626G>A	p.Gly542Gly	synonymous_variant	Exon 12 of 46	5		ENSP00000490223.1
CACNA1A	ENST00000637736.1	c.1485G>A	p.Gly495Gly	synonymous_variant	Exon 11 of 46	5		ENSP00000489861.1
CACNA1A	ENST00000636389.1	c.1626G>A	p.Gly542Gly	synonymous_variant	Exon 12 of 47	5		ENSP00000489992.1
CACNA1A	ENST00000637432.1	c.1626G>A	p.Gly542Gly	synonymous_variant	Exon 12 of 48	5		ENSP00000490617.1
CACNA1A	ENST00000636549.1	c.1626G>A	p.Gly542Gly	synonymous_variant	Exon 12 of 48	5		ENSP00000490578.1
CACNA1A	ENST00000637927.1	c.1629G>A	p.Gly543Gly	synonymous_variant	Exon 12 of 47	5		ENSP00000489715.1
CACNA1A	ENST00000635895.1	c.1626G>A	p.Gly542Gly	synonymous_variant	Exon 12 of 47	5		ENSP00000490323.1
CACNA1A	ENST00000638009.2	c.1626G>A	p.Gly542Gly	synonymous_variant	Exon 12 of 47	1		ENSP00000489913.1
CACNA1A	ENST00000637276.1	c.1626G>A	p.Gly542Gly	synonymous_variant	Exon 12 of 46	5		ENSP00000489777.1

Frequencies

GnomAD3 genomes AF: 0.00122 AC: 186 AN: 152148 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00387

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00198

Gnomad OTH AF: 0.00143

GnomAD3 exomes AF: 0.00128 AC: 302 AN: 235208 Hom.: 1 AF XY: 0.00130 AC XY: 167 AN XY: 128162

Gnomad AFR exome AF: 0.0000698

Gnomad AMR exome AF: 0.000162

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00435

Gnomad NFE exome AF: 0.00177

Gnomad OTH exome AF: 0.00197

GnomAD4 exome AF: 0.000975 AC: 1410 AN: 1445760 Hom.: 7 Cov.: 29 AF XY: 0.000992 AC XY: 713 AN XY: 718922

Gnomad4 AFR exome AF: 0.0000932

Gnomad4 AMR exome AF: 0.000167

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000121

Gnomad4 FIN exome AF: 0.00546

Gnomad4 NFE exome AF: 0.000945

Gnomad4 OTH exome AF: 0.00105

GnomAD4 genome AF: 0.00122 AC: 186 AN: 152266 Hom.: 1 Cov.: 32 AF XY: 0.00125 AC XY: 93 AN XY: 74444

Gnomad4 AFR AF: 0.000120

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00387

Gnomad4 NFE AF: 0.00198

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.00192 Hom.: 2

Bravo AF: 0.000623

Asia WGS AF: 0.000289 AC: 1 AN: 3478

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

Mar 27, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 12, 2013

Eurofins Ntd Llc (ga)

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

CACNA1A: BP4, BP7 -

not specified Benign:1

Feb 18, 2021

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

Jan 28, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Inborn genetic diseases Benign:1

Feb 10, 2017

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Sep 06, 2019

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as 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	-0.30
CADD	Benign	9.2
DANN	Benign	0.69

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: rs375628894; hg19: chr19-13423528;