rs16051

chr19-13208879-A-Cchr19-13208879-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2 PP2 BP4

The NM_001127222.2(CACNA1A):c.6657T>G(p.His2219Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H2219P) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 27)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: CACNA1A NM_001127222.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.00

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 Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, CACNA1A
• BP4: Computational evidence support a benign effect (MetaRNN=0.35244128).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CACNA1A	NM_001127222.2	c.6657T>G	p.His2219Gln	missense_variant	46/47	ENST00000360228.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CACNA1A	ENST00000360228.11	c.6657T>G	p.His2219Gln	missense_variant	46/47	1	NM_001127222.2

Frequencies

GnomAD3 genomes Cov.: 27

GnomAD4 exome Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0 AN: 1305510 Hom.: 0 Cov.: 66 AF XY: 0.00 AC XY: 0 AN XY: 645420

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 27

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.27
BayesDel_addAF	Uncertain	0.097	D
BayesDel_noAF	Benign	-0.10
Cadd	Benign	15
Dann	Benign	0.97
Eigen	Benign	-0.38
Eigen_PC	Benign	-0.45
FATHMM_MKL	Benign	0.51	D
LIST_S2	Benign	0.83	T;T;T;D;D;T;T;D;T;D;.;T;T;T;D;D;T;D
M_CAP	Pathogenic	0.87	D
MetaRNN	Benign	0.35	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Uncertain	0.23	D
MutationTaster	Benign	0.98	N;N;N
PrimateAI	Pathogenic	0.85	D
Sift4G	Benign	0.28	T;T;.;.;.;T;.;.;.;.;.;.;.;.;.;.;.;.
Vest4		0.13
MutPred		0.21		.;.;Gain of glycosylation at P2222 (P = 0.1505);Gain of glycosylation at P2222 (P = 0.1505);Gain of glycosylation at P2222 (P = 0.1505);.;.;Gain of glycosylation at P2222 (P = 0.1505);.;.;.;.;Gain of glycosylation at P2222 (P = 0.1505);.;.;.;.;.;
MVP		0.85
MPC		0.49
ClinPred		0.27	T
Varity_R		0.081
gMVP		0.17

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs16051; hg19: chr19-13319693;