rs369920914

Variant names:

• chr19-13317254-C-G
• rs369920914
• NM_001127222.2:c.1413G>C

Your query was ambiguous. Multiple possible variants found:

• chr19-13317254-C-G
• chr19-13317254-C-T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001127222.2(CACNA1A):​c.1413G>C​(p.Lys471Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,132 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. K471T) has been classified as Uncertain significance.

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
• Consequence: CACNA1A NM_001127222.2 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: -0.0310
• Publications: 1 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

ENSG00000306107 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.2879867).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1A	NM_001127222.2	c.1413G>C	p.Lys471Asn	missense_variant	Exon 11 of 47	ENST00000360228.11	NP_001120694.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CACNA1A	ENST00000360228.11	c.1413G>C	p.Lys471Asn	missense_variant	Exon 11 of 47	1	NM_001127222.2	ENSP00000353362.5
CACNA1A	ENST00000638029.1	c.1416G>C	p.Lys472Asn	missense_variant	Exon 11 of 48	5		ENSP00000489829.1
CACNA1A	ENST00000573710.7	c.1419G>C	p.Lys473Asn	missense_variant	Exon 11 of 47	5		ENSP00000460092.3
CACNA1A	ENST00000635727.1	c.1416G>C	p.Lys472Asn	missense_variant	Exon 11 of 47	5		ENSP00000490001.1
CACNA1A	ENST00000637769.1	c.1416G>C	p.Lys472Asn	missense_variant	Exon 11 of 47	1		ENSP00000489778.1
CACNA1A	ENST00000636012.1	c.1416G>C	p.Lys472Asn	missense_variant	Exon 11 of 46	5		ENSP00000490223.1
CACNA1A	ENST00000637736.1	c.1275G>C	p.Lys425Asn	missense_variant	Exon 10 of 46	5		ENSP00000489861.1
CACNA1A	ENST00000636389.1	c.1416G>C	p.Lys472Asn	missense_variant	Exon 11 of 47	5		ENSP00000489992.1
CACNA1A	ENST00000637432.1	c.1416G>C	p.Lys472Asn	missense_variant	Exon 11 of 48	5		ENSP00000490617.1
CACNA1A	ENST00000636549.1	c.1416G>C	p.Lys472Asn	missense_variant	Exon 11 of 48	5		ENSP00000490578.1
CACNA1A	ENST00000637927.1	c.1419G>C	p.Lys473Asn	missense_variant	Exon 11 of 47	5		ENSP00000489715.1
CACNA1A	ENST00000635895.1	c.1416G>C	p.Lys472Asn	missense_variant	Exon 11 of 47	5		ENSP00000490323.1
CACNA1A	ENST00000638009.2	c.1416G>C	p.Lys472Asn	missense_variant	Exon 11 of 47	1		ENSP00000489913.1
CACNA1A	ENST00000637276.1	c.1416G>C	p.Lys472Asn	missense_variant	Exon 11 of 46	5		ENSP00000489777.1
CACNA1A	ENST00000636768.2	n.1416G>C		non_coding_transcript_exon_variant	Exon 11 of 45	5		ENSP00000490190.2
CACNA1A	ENST00000713789.1	n.1413G>C		non_coding_transcript_exon_variant	Exon 11 of 47			ENSP00000519091.1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152132 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 31

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152132 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74324

African (AFR) AF: 0.0000241 AC: 1 AN: 41430

American (AMR) AF: 0.00 AC: 0 AN: 15254

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5196

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10602

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68030

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ESP6500AA AF: 0.000257 AC: 1

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00000827 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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

Feb 08, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces lysine with asparagine at codon 472 of the CACNA1A protein (p.Lys472Asn). The lysine residue is highly conserved and there is a moderate physicochemical difference between lysine and asparagine. This variant is present in population databases (rs369920914, ExAC 0.01%). This variant has not been reported in the literature in individuals with CACNA1A-related disease. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

not provided Uncertain:1

Mar 15, 2024

Athena Diagnostics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Available data are insufficient to determine the clinical significance of the variant at this time. The frequency of this variant in the general population is uninformative in assessment of its pathogenicity. (http://gnomad.broadinstitute.org) Computational tools predict that this variant is not damaging. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.83
BayesDel_addAF	Uncertain	0.074	D
BayesDel_noAF	Benign	-0.13
CADD	Benign	19
DANN	Benign	0.96
DEOGEN2	Uncertain	0.52	.;D;T;.;.;.;.;.;.;T;.;.;.;T;.
Eigen	Benign	-0.80
Eigen_PC	Benign	-0.74
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.91	D;D;D;D;D;D;D;D;.;D;D;D;D;D;D
M_CAP	Uncertain	0.22	D
MetaRNN	Benign	0.29	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Uncertain	0.17	D
MutationAssessor	Pathogenic	3.0	.;.;.;.;M;.;.;M;.;.;.;.;M;.;.
PhyloP100		-0.031
PrimateAI	Uncertain	0.78	T
PROVEAN	Pathogenic	-4.4	.;D;.;.;.;.;.;.;.;.;.;.;.;.;.
REVEL	Uncertain	0.45
Sift	Benign	0.13	.;T;.;.;.;.;.;.;.;.;.;.;.;.;.
Sift4G	Benign	0.095	T;T;.;.;.;.;.;.;.;.;.;.;.;.;.
Vest4		0.35
MutPred		0.48		Loss of methylation at K472 (P = 0.0014);.;Loss of methylation at K472 (P = 0.0014);Loss of methylation at K472 (P = 0.0014);Loss of methylation at K472 (P = 0.0014);.;Loss of methylation at K472 (P = 0.0014);Loss of methylation at K472 (P = 0.0014);Loss of methylation at K472 (P = 0.0014);Loss of methylation at K472 (P = 0.0014);Loss of methylation at K472 (P = 0.0014);.;Loss of methylation at K472 (P = 0.0014);.;Loss of methylation at K472 (P = 0.0014);
MVP		0.90
MPC		2.3
ClinPred		0.33	T
GERP RS		2.4
Varity_R		0.28
gMVP		0.70
Mutation Taster		=64/36	polymorphism

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: rs369920914; hg19: chr19-13428068;