rs16023

Variant names:

• chr19-13298658-T-A
• rs16023
• NM_001127222.2:c.2975A>T

Your query was ambiguous. Multiple possible variants found:

• chr19-13298658-T-A
• chr19-13298658-T-C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001127222.2(CACNA1A):​c.2975A>T​(p.Glu992Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.143 in 1,502,488 control chromosomes in the GnomAD database, including 15,900 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E992Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.13 (1408 hom., cov: 32)
  • Exomes 𝑓: 0.14 (14492 hom.)
• Consequence: CACNA1A NM_001127222.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:13 O:1
• Conservation: PhyloP100: 2.84
• Publications: 22 publications found

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 Gene-Disease associations (from GenCC):

• episodic ataxia type 2

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Ambry Genetics, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
• undetermined early-onset epileptic encephalopathy

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, Illumina
• developmental and epileptic encephalopathy, 42

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• migraine, familial hemiplegic, 1

  Inheritance: AD Classification: STRONG Submitted by: Ambry Genetics, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
• spinocerebellar ataxia type 6

  Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Ambry Genetics, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Orphanet
• benign paroxysmal torticollis of infancy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• familial or sporadic hemiplegic migraine

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Lennox-Gastaut syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0017878115).
• BP6: Variant 19-13298658-T-A is Benign according to our data. Variant chr19-13298658-T-A is described in ClinVar as [Benign]. Clinvar id is 68427.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.148 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1A	NM_001127222.2	c.2975A>T	p.Glu992Val	missense_variant	Exon 19 of 47	ENST00000360228.11	NP_001120694.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CACNA1A	ENST00000360228.11	c.2975A>T	p.Glu992Val	missense_variant	Exon 19 of 47	1	NM_001127222.2	ENSP00000353362.5
CACNA1A	ENST00000638029.1	c.2987A>T	p.Glu996Val	missense_variant	Exon 19 of 48	5		ENSP00000489829.1
CACNA1A	ENST00000573710.7	c.2981A>T	p.Glu994Val	missense_variant	Exon 19 of 47	5		ENSP00000460092.3
CACNA1A	ENST00000635727.1	c.2978A>T	p.Glu993Val	missense_variant	Exon 19 of 47	5		ENSP00000490001.1
CACNA1A	ENST00000637769.1	c.2978A>T	p.Glu993Val	missense_variant	Exon 19 of 47	1		ENSP00000489778.1
CACNA1A	ENST00000636012.1	c.2978A>T	p.Glu993Val	missense_variant	Exon 19 of 46	5		ENSP00000490223.1
CACNA1A	ENST00000637736.1	c.2837A>T	p.Glu946Val	missense_variant	Exon 18 of 46	5		ENSP00000489861.1
CACNA1A	ENST00000636389.1	c.2978A>T	p.Glu993Val	missense_variant	Exon 19 of 47	5		ENSP00000489992.1
CACNA1A	ENST00000637432.1	c.2987A>T	p.Glu996Val	missense_variant	Exon 19 of 48	5		ENSP00000490617.1
CACNA1A	ENST00000636549.1	c.2978A>T	p.Glu993Val	missense_variant	Exon 19 of 48	5		ENSP00000490578.1
CACNA1A	ENST00000637927.1	c.2981A>T	p.Glu994Val	missense_variant	Exon 19 of 47	5		ENSP00000489715.1
CACNA1A	ENST00000635895.1	c.2978A>T	p.Glu993Val	missense_variant	Exon 19 of 47	5		ENSP00000490323.1
CACNA1A	ENST00000638009.2	c.2978A>T	p.Glu993Val	missense_variant	Exon 19 of 47	1		ENSP00000489913.1
CACNA1A	ENST00000637276.1	c.2978A>T	p.Glu993Val	missense_variant	Exon 19 of 46	5		ENSP00000489777.1
CACNA1A	ENST00000636768.2	n.2978A>T		non_coding_transcript_exon_variant	Exon 19 of 45	5		ENSP00000490190.2
CACNA1A	ENST00000713789.1	n.2975A>T		non_coding_transcript_exon_variant	Exon 19 of 47			ENSP00000519091.1

Frequencies

GnomAD3 genomes AF: 0.134 AC: 20277 AN: 151782 Hom.: 1410 Cov.: 32

Gnomad AFR AF: 0.105

Gnomad AMI AF: 0.163

Gnomad AMR AF: 0.141

Gnomad ASJ AF: 0.161

Gnomad EAS AF: 0.123

Gnomad SAS AF: 0.120

Gnomad FIN AF: 0.123

Gnomad MID AF: 0.182

Gnomad NFE AF: 0.151

Gnomad OTH AF: 0.149

GnomAD2 exomes AF: 0.137 AC: 14100 AN: 102910 AF XY: 0.134

Gnomad AFR exome AF: 0.112

Gnomad AMR exome AF: 0.146

Gnomad ASJ exome AF: 0.164

Gnomad EAS exome AF: 0.0934

Gnomad FIN exome AF: 0.121

Gnomad NFE exome AF: 0.148

Gnomad OTH exome AF: 0.177

GnomAD4 exome AF: 0.144 AC: 194404 AN: 1350598 Hom.: 14492 Cov.: 32 AF XY: 0.144 AC XY: 95757 AN XY: 666138

African (AFR) AF: 0.0978 AC: 2641 AN: 27012

American (AMR) AF: 0.147 AC: 4253 AN: 28944

Ashkenazi Jewish (ASJ) AF: 0.163 AC: 3820 AN: 23430

East Asian (EAS) AF: 0.153 AC: 4545 AN: 29706

South Asian (SAS) AF: 0.116 AC: 8669 AN: 74636

European-Finnish (FIN) AF: 0.121 AC: 5745 AN: 47320

Middle Eastern (MID) AF: 0.202 AC: 1109 AN: 5500

European-Non Finnish (NFE) AF: 0.147 AC: 155295 AN: 1058490

Other (OTH) AF: 0.150 AC: 8327 AN: 55560

GnomAD4 genome AF: 0.133 AC: 20272 AN: 151890 Hom.: 1408 Cov.: 32 AF XY: 0.132 AC XY: 9802 AN XY: 74268

African (AFR) AF: 0.104 AC: 4330 AN: 41470

American (AMR) AF: 0.141 AC: 2145 AN: 15258

Ashkenazi Jewish (ASJ) AF: 0.161 AC: 558 AN: 3466

East Asian (EAS) AF: 0.123 AC: 629 AN: 5130

South Asian (SAS) AF: 0.120 AC: 578 AN: 4830

European-Finnish (FIN) AF: 0.123 AC: 1293 AN: 10518

Middle Eastern (MID) AF: 0.182 AC: 53 AN: 292

European-Non Finnish (NFE) AF: 0.151 AC: 10226 AN: 67908

Other (OTH) AF: 0.148 AC: 312 AN: 2108

Alfa AF: 0.145 Hom.: 532

Bravo AF: 0.135

TwinsUK AF: 0.138 AC: 512

ALSPAC AF: 0.146 AC: 563

ESP6500AA AF: 0.0930 AC: 230

ESP6500EA AF: 0.128 AC: 655

ExAC AF: 0.112 AC: 2507

Asia WGS AF: 0.113 AC: 392 AN: 3466

ClinVar

Significance: Benign

Submissions summary: Benign:13 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:10

Jul 15, 2024

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is classified as Benign based on local population frequency. This variant was detected in 30% of patients studied in a panel designed for Epileptic and Developmental Encephalopathy and Progressive Myoclonus Epilepsy. Number of patients: 28. Only high quality variants are reported. -

-

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

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. -

May 03, 2021

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 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. -

Mar 18, 2014

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not provided Benign:1 Other:1

-

UniProtKB/Swiss-Prot

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

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

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Inborn genetic diseases Benign:1

Mar 11, 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.23
BayesDel_addAF	Benign	-0.38	T
BayesDel_noAF	Benign	-0.18
CADD	Benign	22
DANN	Benign	0.91
DEOGEN2	Benign	0.031	.;.;T;.;.;.;.;.;.;T;.;.;.;T;.
Eigen	Benign	-0.31
Eigen_PC	Benign	-0.29
FATHMM_MKL	Benign	0.43	N
LIST_S2	Benign	0.69	T;T;T;T;T;T;T;T;.;T;T;T;T;T;T
MetaRNN	Benign	0.0018	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.61	T
MutationAssessor	Benign	1.1	.;.;.;.;L;.;.;.;.;.;.;.;L;.;.
PhyloP100		2.8
PrimateAI	Pathogenic	0.87	D
PROVEAN	Benign	-1.7	.;N;.;.;.;.;.;.;.;.;.;.;.;.;.
REVEL	Benign	0.28
Sift	Uncertain	0.029	.;D;.;.;.;.;.;.;.;.;.;.;.;.;.
Sift4G	Benign	0.16	T;T;.;.;.;.;.;.;.;.;.;.;.;.;.
Vest4		0.094
MPC		2.0
ClinPred		0.016	T
GERP RS		3.9
Varity_R		0.17
gMVP		0.52
Mutation Taster		=91/9	polymorphism (auto)

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

Other links and lift over

dbSNP: rs16023; hg19: chr19-13409472; COSMIC: COSV64201171;