19-13207394-G-C

Position:

• chr19-13207394-G-C

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.7440C>G​(p.His2480Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00215 in 1,538,980 control chromosomes in the GnomAD database, including 10 homozygotes. 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 (★★). Synonymous variant affecting the same amino acid position (i.e. H2480H) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0016 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0022 (10 hom.)
• Consequence: CACNA1A NM_001127222.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.349

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 where missense usually causes diseases, CACNA1A
• BP4: Computational evidence support a benign effect (MetaRNN=0.012342066).
• BP6: Variant 19-13207394-G-C is Benign according to our data. Variant chr19-13207394-G-C is described in ClinVar as [Likely_benign]. Clinvar id is 994534.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-13207394-G-C is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00164 (248/151620) while in subpopulation NFE AF= 0.00314 (213/67752). AF 95% confidence interval is 0.0028. There are 0 homozygotes in gnomad4. There are 113 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 248 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CACNA1A	NM_001127222.2	c.7440C>G	p.His2480Gln	missense_variant	47/47	ENST00000360228.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CACNA1A	ENST00000360228.11	c.7440C>G	p.His2480Gln	missense_variant	47/47	1	NM_001127222.2

Frequencies

GnomAD3 genomes AF: 0.00164 AC: 248 AN: 151512 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.000339

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000460

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000830

Gnomad FIN AF: 0.000856

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00314

Gnomad OTH AF: 0.000480

GnomAD3 exomes AF: 0.00150 AC: 213 AN: 141688 Hom.: 1 AF XY: 0.00160 AC XY: 126 AN XY: 78582

Gnomad AFR exome AF: 0.000321

Gnomad AMR exome AF: 0.000356

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000645

Gnomad FIN exome AF: 0.000913

Gnomad NFE exome AF: 0.00305

Gnomad OTH exome AF: 0.00189

GnomAD4 exome AF: 0.00221 AC: 3061 AN: 1387360 Hom.: 10 Cov.: 30 AF XY: 0.00218 AC XY: 1500 AN XY: 686664

Gnomad4 AFR exome AF: 0.000257

Gnomad4 AMR exome AF: 0.000273

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000760

Gnomad4 FIN exome AF: 0.00119

Gnomad4 NFE exome AF: 0.00258

Gnomad4 OTH exome AF: 0.00260

GnomAD4 genome AF: 0.00164 AC: 248 AN: 151620 Hom.: 0 Cov.: 31 AF XY: 0.00152 AC XY: 113 AN XY: 74148

Gnomad4 AFR AF: 0.000338

Gnomad4 AMR AF: 0.000459

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000831

Gnomad4 FIN AF: 0.000856

Gnomad4 NFE AF: 0.00314

Gnomad4 OTH AF: 0.000475

Alfa AF: 0.00134 Hom.: 0

Bravo AF: 0.00133

ExAC AF: 0.00108 AC: 113

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2024	CACNA1A: PP3, BS1 -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Athena Diagnostics

Aug 14, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.21
CADD	Benign	15
DANN	Benign	0.87
Eigen	Benign	-0.80
Eigen_PC	Benign	-0.69
FATHMM_MKL	Benign	0.60	D
LIST_S2	Benign	0.65	T;T;T;T;T;T;.;T;T;T
M_CAP	Pathogenic	0.97	D
MetaRNN	Benign	0.012	T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.34	T
MutationTaster	Benign	1.0	D;N;N
PrimateAI	Pathogenic	0.93	D
Sift4G	Benign	0.45	T;T;.;T;.;.;.;.;.;.
Vest4		0.093
MutPred		0.17		.;Loss of solvent accessibility (P = 0.0468);.;.;.;.;.;.;.;.;
MVP		0.69
MPC		0.28
ClinPred		0.0013	T
GERP RS		0.82
Varity_R		0.058
gMVP		0.26

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: rs539546830; hg19: chr19-13318208;