rs16044

Variant names:

• chr19-13214601-G-A
• rs16044
• NM_001127222.2:c.5739C>T

Your query was ambiguous. Multiple possible variants found:

• chr19-13214601-G-A
• chr19-13214601-G-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.5739C>T​(p.Ala1913Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00244 in 1,612,970 control chromosomes in the GnomAD database, including 75 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.013 (35 hom., cov: 32)
  • Exomes 𝑓: 0.0013 (40 hom.)
• Consequence: CACNA1A NM_001127222.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -4.58

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=-0.8).
• BP6: Variant 19-13214601-G-A is Benign according to our data. Variant chr19-13214601-G-A is described in ClinVar as [Benign]. Clinvar id is 128555.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-13214601-G-A is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-4.58 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0131 (2001/152284) while in subpopulation AFR AF= 0.0457 (1900/41568). AF 95% confidence interval is 0.044. There are 35 homozygotes in gnomad4. There are 918 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 2001 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1A	NM_001127222.2	c.5739C>T	p.Ala1913Ala	synonymous_variant	Exon 39 of 47	ENST00000360228.11	NP_001120694.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CACNA1A	ENST00000360228.11	c.5739C>T	p.Ala1913Ala	synonymous_variant	Exon 39 of 47	1	NM_001127222.2	ENSP00000353362.5
CACNA1A	ENST00000638029.1	c.5757C>T	p.Ala1919Ala	synonymous_variant	Exon 40 of 48	5		ENSP00000489829.1
CACNA1A	ENST00000573710.7	c.5745C>T	p.Ala1915Ala	synonymous_variant	Exon 39 of 47	5		ENSP00000460092.3
CACNA1A	ENST00000635727.1	c.5742C>T	p.Ala1914Ala	synonymous_variant	Exon 39 of 47	5		ENSP00000490001.1
CACNA1A	ENST00000637769.1	c.5742C>T	p.Ala1914Ala	synonymous_variant	Exon 39 of 47	1		ENSP00000489778.1
CACNA1A	ENST00000636012.1	c.5742C>T	p.Ala1914Ala	synonymous_variant	Exon 39 of 46	5		ENSP00000490223.1
CACNA1A	ENST00000637736.1	c.5601C>T	p.Ala1867Ala	synonymous_variant	Exon 38 of 46	5		ENSP00000489861.1
CACNA1A	ENST00000636389.1	c.5742C>T	p.Ala1914Ala	synonymous_variant	Exon 39 of 47	5		ENSP00000489992.1
CACNA1A	ENST00000637432.1	c.5757C>T	p.Ala1919Ala	synonymous_variant	Exon 40 of 48	5		ENSP00000490617.1
CACNA1A	ENST00000636549.1	c.5748C>T	p.Ala1916Ala	synonymous_variant	Exon 40 of 48	5		ENSP00000490578.1
CACNA1A	ENST00000637927.1	c.5745C>T	p.Ala1915Ala	synonymous_variant	Exon 39 of 47	5		ENSP00000489715.1
CACNA1A	ENST00000635895.1	c.5742C>T	p.Ala1914Ala	synonymous_variant	Exon 39 of 47	5		ENSP00000490323.1
CACNA1A	ENST00000638009.2	c.5742C>T	p.Ala1914Ala	synonymous_variant	Exon 39 of 47	1		ENSP00000489913.1
CACNA1A	ENST00000637276.1	c.5742C>T	p.Ala1914Ala	synonymous_variant	Exon 39 of 46	5		ENSP00000489777.1
CACNA1A	ENST00000636768.1	n.*41C>T		non_coding_transcript_exon_variant	Exon 4 of 10	5		ENSP00000490190.2
CACNA1A	ENST00000636768.1	n.*41C>T		3_prime_UTR_variant	Exon 4 of 10	5		ENSP00000490190.2

Frequencies

GnomAD3 genomes AF: 0.0131 AC: 1999 AN: 152166 Hom.: 34 Cov.: 32

Gnomad AFR AF: 0.0458

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00426

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000188

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000103

Gnomad OTH AF: 0.0124

GnomAD3 exomes AF: 0.00322 AC: 798 AN: 247506 Hom.: 11 AF XY: 0.00237 AC XY: 319 AN XY: 134330

Gnomad AFR exome AF: 0.0449

Gnomad AMR exome AF: 0.00233

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000990

Gnomad FIN exome AF: 0.0000933

Gnomad NFE exome AF: 0.000151

Gnomad OTH exome AF: 0.00149

GnomAD4 exome AF: 0.00133 AC: 1937 AN: 1460686 Hom.: 40 Cov.: 31 AF XY: 0.00115 AC XY: 839 AN XY: 726578

Gnomad4 AFR exome AF: 0.0462

Gnomad4 AMR exome AF: 0.00211

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000128

Gnomad4 FIN exome AF: 0.000131

Gnomad4 NFE exome AF: 0.0000765

Gnomad4 OTH exome AF: 0.00297

GnomAD4 genome AF: 0.0131 AC: 2001 AN: 152284 Hom.: 35 Cov.: 32 AF XY: 0.0123 AC XY: 918 AN XY: 74458

Gnomad4 AFR AF: 0.0457

Gnomad4 AMR AF: 0.00425

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000188

Gnomad4 NFE AF: 0.000103

Gnomad4 OTH AF: 0.0123

Alfa AF: 0.00285 Hom.: 7

Bravo AF: 0.0143

Asia WGS AF: 0.00260 AC: 9 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.000238

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Jun 15, 2021

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 05, 2016

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

-

Genetic Services Laboratory, University of Chicago

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

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. -

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

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Inborn genetic diseases Benign:1

Jan 08, 2016

Ambry Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

CACNA1A-related disorder Benign:1

Jul 01, 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	-0.80
CADD	Benign	0.74
DANN	Benign	0.46

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: rs16044; hg19: chr19-13325415;