rs16022

Positions:

• chr19-13298882-C-G
• chr19-13298882-C-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2 BP4_Strong BP6_Very_Strong BA1

The NM_001127222.2(CACNA1A):​c.2751G>C​(p.Glu917Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.138 in 1,592,562 control chromosomes in the GnomAD database, including 15,785 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. E917E) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.12 (1247 hom., cov: 32)
  • Exomes 𝑓: 0.14 (14538 hom.)
• Consequence: CACNA1A NM_001127222.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:12 O:1
• Conservation: PhyloP100: 0.00200

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 -19 ACMG points.

• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), CACNA1A. . Gene score misZ 5.7845 (greater than the threshold 3.09). Trascript score misZ 3.9354 (greater than threshold 3.09). GenCC has associacion of gene with benign paroxysmal torticollis of infancy, developmental and epileptic encephalopathy, 42, undetermined early-onset epileptic encephalopathy, episodic ataxia type 2, familial or sporadic hemiplegic migraine, spinocerebellar ataxia type 6, Lennox-Gastaut syndrome, migraine, familial hemiplegic, 1.
• BP4: Computational evidence support a benign effect (MetaRNN=0.0017104447).
• BP6: Variant 19-13298882-C-G is Benign according to our data. Variant chr19-13298882-C-G is described in ClinVar as [Benign]. Clinvar id is 68426.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-13298882-C-G is described in Lovd as [Benign]. Variant chr19-13298882-C-G is described in Lovd as [Likely_benign].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.144 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CACNA1A	NM_001127222.2	c.2751G>C	p.Glu917Asp	missense_variant	19/47	ENST00000360228.11	NP_001120694.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CACNA1A	ENST00000360228.11	c.2751G>C	p.Glu917Asp	missense_variant	19/47	1	NM_001127222.2	ENSP00000353362.5
CACNA1A	ENST00000638029.1	c.2763G>C	p.Glu921Asp	missense_variant	19/48	5		ENSP00000489829.1
CACNA1A	ENST00000573710.7	c.2757G>C	p.Glu919Asp	missense_variant	19/47	5		ENSP00000460092.3
CACNA1A	ENST00000635727.1	c.2754G>C	p.Glu918Asp	missense_variant	19/47	5		ENSP00000490001.1
CACNA1A	ENST00000637769.1	c.2754G>C	p.Glu918Asp	missense_variant	19/47	1		ENSP00000489778.1
CACNA1A	ENST00000636012.1	c.2754G>C	p.Glu918Asp	missense_variant	19/46	5		ENSP00000490223.1
CACNA1A	ENST00000637736.1	c.2613G>C	p.Glu871Asp	missense_variant	18/46	5		ENSP00000489861.1
CACNA1A	ENST00000636389.1	c.2754G>C	p.Glu918Asp	missense_variant	19/47	5		ENSP00000489992.1
CACNA1A	ENST00000637432.1	c.2763G>C	p.Glu921Asp	missense_variant	19/48	5		ENSP00000490617.1
CACNA1A	ENST00000636549.1	c.2754G>C	p.Glu918Asp	missense_variant	19/48	5		ENSP00000490578.1
CACNA1A	ENST00000637927.1	c.2757G>C	p.Glu919Asp	missense_variant	19/47	5		ENSP00000489715.1
CACNA1A	ENST00000635895.1	c.2754G>C	p.Glu918Asp	missense_variant	19/47	5		ENSP00000490323.1
CACNA1A	ENST00000638009.2	c.2754G>C	p.Glu918Asp	missense_variant	19/47	1		ENSP00000489913.1
CACNA1A	ENST00000637276.1	c.2754G>C	p.Glu918Asp	missense_variant	19/46	5		ENSP00000489777.1

Frequencies

GnomAD3 genomes AF: 0.122 AC: 18593 AN: 152102 Hom.: 1247 Cov.: 32

Gnomad AFR AF: 0.0721

Gnomad AMI AF: 0.162

Gnomad AMR AF: 0.136

Gnomad ASJ AF: 0.154

Gnomad EAS AF: 0.123

Gnomad SAS AF: 0.120

Gnomad FIN AF: 0.123

Gnomad MID AF: 0.162

Gnomad NFE AF: 0.147

Gnomad OTH AF: 0.140

GnomAD3 exomes AF: 0.126 AC: 27267 AN: 215748 Hom.: 1777 AF XY: 0.125 AC XY: 15073 AN XY: 120314

Gnomad AFR exome AF: 0.0630

Gnomad AMR exome AF: 0.137

Gnomad ASJ exome AF: 0.151

Gnomad EAS exome AF: 0.0982

Gnomad SAS exome AF: 0.110

Gnomad FIN exome AF: 0.112

Gnomad NFE exome AF: 0.139

Gnomad OTH exome AF: 0.139

GnomAD4 exome AF: 0.140 AC: 201088 AN: 1440352 Hom.: 14538 Cov.: 33 AF XY: 0.139 AC XY: 99703 AN XY: 716648

Gnomad4 AFR exome AF: 0.0667

Gnomad4 AMR exome AF: 0.141

Gnomad4 ASJ exome AF: 0.153

Gnomad4 EAS exome AF: 0.142

Gnomad4 SAS exome AF: 0.115

Gnomad4 FIN exome AF: 0.120

Gnomad4 NFE exome AF: 0.144

Gnomad4 OTH exome AF: 0.143

GnomAD4 genome AF: 0.122 AC: 18601 AN: 152210 Hom.: 1247 Cov.: 32 AF XY: 0.121 AC XY: 9005 AN XY: 74422

Gnomad4 AFR AF: 0.0722

Gnomad4 AMR AF: 0.136

Gnomad4 ASJ AF: 0.154

Gnomad4 EAS AF: 0.122

Gnomad4 SAS AF: 0.120

Gnomad4 FIN AF: 0.123

Gnomad4 NFE AF: 0.147

Gnomad4 OTH AF: 0.139

Alfa AF: 0.0877 Hom.: 185

Bravo AF: 0.121

TwinsUK AF: 0.135 AC: 501

ALSPAC AF: 0.141 AC: 545

ESP6500AA AF: 0.0585 AC: 206

ESP6500EA AF: 0.116 AC: 883

ExAC AF: 0.119 AC: 13837

Asia WGS AF: 0.115 AC: 397 AN: 3462

ClinVar

Significance: Benign

Submissions summary: Benign:12 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:9

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Mar 18, 2014	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 05, 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. -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	May 03, 2021	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan	Jul 15, 2024	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. -
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. -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

not provided Benign:1 Other:1

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
not provided, no classification provided	literature only	UniProtKB/Swiss-Prot	-	- -

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

Mar 16, 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.083
BayesDel_addAF	Benign	-0.51	T
BayesDel_noAF	Benign	-0.37
CADD	Benign	11
DANN	Benign	0.58
DEOGEN2	Benign	0.024	.;.;T;.;.;.;.;.;.;T;.;.;.;T;.
Eigen	Benign	-0.90
Eigen_PC	Benign	-0.82
FATHMM_MKL	Benign	0.032	N
LIST_S2	Benign	0.59	T;T;T;T;T;T;T;T;.;T;T;T;T;T;T
MetaRNN	Benign	0.0017	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.49	T
MutationAssessor	Benign	0.90	.;.;.;.;L;.;.;.;.;.;.;.;L;.;.
PrimateAI	Uncertain	0.78	T
PROVEAN	Benign	-0.66	.;N;.;.;.;.;.;.;.;.;.;.;.;.;.
REVEL	Benign	0.25
Sift	Benign	0.43	.;T;.;.;.;.;.;.;.;.;.;.;.;.;.
Sift4G	Benign	0.11	T;T;.;.;.;.;.;.;.;.;.;.;.;.;.
Vest4		0.013
MutPred		0.17		.;.;Gain of MoRF binding (P = 0.2255);Gain of MoRF binding (P = 0.2255);Gain of MoRF binding (P = 0.2255);.;Gain of MoRF binding (P = 0.2255);.;.;Gain of MoRF binding (P = 0.2255);Gain of MoRF binding (P = 0.2255);.;Gain of MoRF binding (P = 0.2255);.;Gain of MoRF binding (P = 0.2255);
MPC		2.0
ClinPred		0.0072	T
GERP RS		1.5
Varity_R		0.045
gMVP		0.37

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs16022; hg19: chr19-13409696; COSMIC: COSV64192678;