19-13298955-C-T

Position:

• chr19-13298955-C-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2 BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001127222.2(CACNA1A):​c.2678G>A​(p.Arg893Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000569 in 1,587,868 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0023 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00039 (0 hom.)
• Consequence: CACNA1A NM_001127222.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.503

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=0.0072229803).
• BP6: Variant 19-13298955-C-T is Benign according to our data. Variant chr19-13298955-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 283510.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-13298955-C-T is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0023 (350/152300) while in subpopulation AFR AF= 0.00647 (269/41574). AF 95% confidence interval is 0.00584. There are 0 homozygotes in gnomad4. There are 183 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 350 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CACNA1A	NM_001127222.2	c.2678G>A	p.Arg893Gln	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.2678G>A	p.Arg893Gln	missense_variant	19/47	1	NM_001127222.2	ENSP00000353362.5
CACNA1A	ENST00000638029.1	c.2690G>A	p.Arg897Gln	missense_variant	19/48	5		ENSP00000489829.1
CACNA1A	ENST00000573710.7	c.2684G>A	p.Arg895Gln	missense_variant	19/47	5		ENSP00000460092.3
CACNA1A	ENST00000635727.1	c.2681G>A	p.Arg894Gln	missense_variant	19/47	5		ENSP00000490001.1
CACNA1A	ENST00000637769.1	c.2681G>A	p.Arg894Gln	missense_variant	19/47	1		ENSP00000489778.1
CACNA1A	ENST00000636012.1	c.2681G>A	p.Arg894Gln	missense_variant	19/46	5		ENSP00000490223.1
CACNA1A	ENST00000637736.1	c.2540G>A	p.Arg847Gln	missense_variant	18/46	5		ENSP00000489861.1
CACNA1A	ENST00000636389.1	c.2681G>A	p.Arg894Gln	missense_variant	19/47	5		ENSP00000489992.1
CACNA1A	ENST00000637432.1	c.2690G>A	p.Arg897Gln	missense_variant	19/48	5		ENSP00000490617.1
CACNA1A	ENST00000636549.1	c.2681G>A	p.Arg894Gln	missense_variant	19/48	5		ENSP00000490578.1
CACNA1A	ENST00000637927.1	c.2684G>A	p.Arg895Gln	missense_variant	19/47	5		ENSP00000489715.1
CACNA1A	ENST00000635895.1	c.2681G>A	p.Arg894Gln	missense_variant	19/47	5		ENSP00000490323.1
CACNA1A	ENST00000638009.2	c.2681G>A	p.Arg894Gln	missense_variant	19/47	1		ENSP00000489913.1
CACNA1A	ENST00000637276.1	c.2681G>A	p.Arg894Gln	missense_variant	19/46	5		ENSP00000489777.1

Frequencies

GnomAD3 genomes AF: 0.00229 AC: 349 AN: 152184 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00649

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00327

Gnomad ASJ AF: 0.00634

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000103

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.00102 AC: 211 AN: 206492 Hom.: 0 AF XY: 0.000861 AC XY: 99 AN XY: 114962

Gnomad AFR exome AF: 0.00701

Gnomad AMR exome AF: 0.00159

Gnomad ASJ exome AF: 0.00743

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000536

Gnomad OTH exome AF: 0.000750

GnomAD4 exome AF: 0.000386 AC: 554 AN: 1435568 Hom.: 0 Cov.: 32 AF XY: 0.000370 AC XY: 264 AN XY: 713652

Gnomad4 AFR exome AF: 0.00675

Gnomad4 AMR exome AF: 0.00155

Gnomad4 ASJ exome AF: 0.00595

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000452

Gnomad4 OTH exome AF: 0.000888

GnomAD4 genome AF: 0.00230 AC: 350 AN: 152300 Hom.: 0 Cov.: 32 AF XY: 0.00246 AC XY: 183 AN XY: 74464

Gnomad4 AFR AF: 0.00647

Gnomad4 AMR AF: 0.00327

Gnomad4 ASJ AF: 0.00634

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000103

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000946 Hom.: 0

Bravo AF: 0.00288

ESP6500AA AF: 0.00256 AC: 9

ESP6500EA AF: 0.000257 AC: 2

ExAC AF: 0.000735 AC: 86

Asia WGS AF: 0.000289 AC: 1 AN: 3468

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Aug 28, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Sep 28, 2015	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 30, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2022	CACNA1A: PP2, PP3, BS1 -

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

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 27, 2024

- -

Inborn genetic diseases Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 21, 2017

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	0.075
BayesDel_addAF	Benign	-0.37	T
BayesDel_noAF	Benign	-0.29
CADD	Uncertain	23
DANN	Benign	0.93
DEOGEN2	Benign	0.020	.;.;T;.;.;.;.;.;.;T;.;.;.;T;.
Eigen	Benign	-0.84
Eigen_PC	Benign	-0.85
FATHMM_MKL	Benign	0.012	N
LIST_S2	Uncertain	0.93	D;D;D;D;D;D;D;D;.;D;D;D;D;D;D
MetaRNN	Benign	0.0072	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Uncertain	0.014	D
MutationAssessor	Benign	1.1	.;.;.;.;L;.;.;.;.;.;.;.;L;.;.
PrimateAI	Pathogenic	0.82	D
PROVEAN	Benign	-0.98	.;N;.;.;.;.;.;.;.;.;.;.;.;.;.
REVEL	Benign	0.27
Sift	Benign	0.17	.;T;.;.;.;.;.;.;.;.;.;.;.;.;.
Sift4G	Benign	0.35	T;T;.;.;.;.;.;.;.;.;.;.;.;.;.
Vest4		0.12
MVP		0.81
MPC		1.7
ClinPred		0.0011	T
GERP RS		1.6
Varity_R		0.039
gMVP		0.48

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: rs374664760; hg19: chr19-13409769;