19-13334406-A-T

Variant names:

• chr19-13334406-A-T
• rs768768744
• NM_001127222.2:c.1170T>A

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PM1 BP4 BS2

The NM_001127222.2(CACNA1A):​c.1170T>A​(p.Asn390Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000826 in 1,453,554 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. N390D) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000083 (0 hom.)
• Consequence: CACNA1A NM_001127222.2 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:4
• Conservation: PhyloP100: -0.310
• Publications: 0 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

ACMG classification

Our verdict: Likely_benign. The variant received -3 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 8 uncertain in NM_001127222.2
• BP4: Computational evidence support a benign effect (MetaRNN=0.39618346).
• BS2: High AC in GnomAdExome4 at 12 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1A	NM_001127222.2	c.1170T>A	p.Asn390Lys	missense_variant	Exon 8 of 47	ENST00000360228.11	NP_001120694.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CACNA1A	ENST00000360228.11	c.1170T>A	p.Asn390Lys	missense_variant	Exon 8 of 47	1	NM_001127222.2	ENSP00000353362.5
CACNA1A	ENST00000638029.1	c.1170T>A	p.Asn390Lys	missense_variant	Exon 8 of 48	5		ENSP00000489829.1
CACNA1A	ENST00000573710.7	c.1170T>A	p.Asn390Lys	missense_variant	Exon 8 of 47	5		ENSP00000460092.3
CACNA1A	ENST00000635727.1	c.1170T>A	p.Asn390Lys	missense_variant	Exon 8 of 47	5		ENSP00000490001.1
CACNA1A	ENST00000637769.1	c.1170T>A	p.Asn390Lys	missense_variant	Exon 8 of 47	1		ENSP00000489778.1
CACNA1A	ENST00000636012.1	c.1170T>A	p.Asn390Lys	missense_variant	Exon 8 of 46	5		ENSP00000490223.1
CACNA1A	ENST00000637736.1	c.1029T>A	p.Asn343Lys	missense_variant	Exon 7 of 46	5		ENSP00000489861.1
CACNA1A	ENST00000636389.1	c.1170T>A	p.Asn390Lys	missense_variant	Exon 8 of 47	5		ENSP00000489992.1
CACNA1A	ENST00000637432.1	c.1170T>A	p.Asn390Lys	missense_variant	Exon 8 of 48	5		ENSP00000490617.1
CACNA1A	ENST00000636549.1	c.1170T>A	p.Asn390Lys	missense_variant	Exon 8 of 48	5		ENSP00000490578.1
CACNA1A	ENST00000637927.1	c.1170T>A	p.Asn390Lys	missense_variant	Exon 8 of 47	5		ENSP00000489715.1
CACNA1A	ENST00000635895.1	c.1170T>A	p.Asn390Lys	missense_variant	Exon 8 of 47	5		ENSP00000490323.1
CACNA1A	ENST00000638009.2	c.1170T>A	p.Asn390Lys	missense_variant	Exon 8 of 47	1		ENSP00000489913.1
CACNA1A	ENST00000637276.1	c.1170T>A	p.Asn390Lys	missense_variant	Exon 8 of 46	5		ENSP00000489777.1
CACNA1A	ENST00000636768.2	n.1170T>A		non_coding_transcript_exon_variant	Exon 8 of 45	5		ENSP00000490190.2
CACNA1A	ENST00000713789.1	n.1170T>A		non_coding_transcript_exon_variant	Exon 8 of 47			ENSP00000519091.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000802 AC: 2 AN: 249276 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000177

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000826 AC: 12 AN: 1453554 Hom.: 0 Cov.: 31 AF XY: 0.00000967 AC XY: 7 AN XY: 723720

African (AFR) AF: 0.00 AC: 0 AN: 33344

American (AMR) AF: 0.00 AC: 0 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26092

East Asian (EAS) AF: 0.00 AC: 0 AN: 39658

South Asian (SAS) AF: 0.00 AC: 0 AN: 86094

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53400

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5762

European-Non Finnish (NFE) AF: 0.0000109 AC: 12 AN: 1104362

Other (OTH) AF: 0.00 AC: 0 AN: 60128

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.0000113

ExAC AF: 0.0000165 AC: 2

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:2

Dec 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

CACNA1A: PP2, PP3 -

Feb 25, 2016

Eurofins Ntd Llc (ga)

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

Nov 09, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces asparagine, which is neutral and polar, with lysine, which is basic and polar, at codon 390 of the CACNA1A protein (p.Asn390Lys). This variant is present in population databases (rs768768744, gnomAD 0.002%). This missense change has been observed in individual(s) with episodic ataxia and migraine (PMID: 34806130). ClinVar contains an entry for this variant (Variation ID: 286277). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt CACNA1A protein function. 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. -

Spinocerebellar ataxia type 6;C1720416:Episodic ataxia type 2;C1832884:Migraine, familial hemiplegic, 1;C4310716:Developmental and epileptic encephalopathy, 42 Uncertain:1

Feb 07, 2022

Fulgent Genetics, Fulgent Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Benign	-0.0075	T
BayesDel_noAF	Benign	-0.23
CADD	Benign	15
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.80	.;D;T;.;.;.;.;.;.;T;.;.;.;T;.
Eigen	Benign	0.018
Eigen_PC	Benign	-0.060
FATHMM_MKL	Benign	0.43	N
LIST_S2	Uncertain	0.87	D;D;D;D;D;D;D;D;.;D;D;D;D;D;D
M_CAP	Benign	0.068	D
MetaRNN	Benign	0.40	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Uncertain	0.14	D
MutationAssessor	Benign	1.4	.;L;.;.;L;.;.;L;.;.;.;.;L;.;.
PhyloP100		-0.31
PrimateAI	Pathogenic	0.87	D
PROVEAN	Pathogenic	-4.6	.;D;.;.;.;.;.;.;.;.;.;.;.;.;.
REVEL	Uncertain	0.49
Sift	Uncertain	0.0030	.;D;.;.;.;.;.;.;.;.;.;.;.;.;.
Sift4G	Benign	0.067	T;T;.;.;.;.;.;.;.;.;.;T;.;.;.
Polyphen		1.0	.;D;.;.;.;.;.;.;.;.;.;.;.;.;.
Vest4		0.62
MutPred		0.48		Gain of helix (P = 0.0199);Gain of helix (P = 0.0199);Gain of helix (P = 0.0199);Gain of helix (P = 0.0199);Gain of helix (P = 0.0199);.;Gain of helix (P = 0.0199);Gain of helix (P = 0.0199);Gain of helix (P = 0.0199);Gain of helix (P = 0.0199);Gain of helix (P = 0.0199);Gain of helix (P = 0.0199);Gain of helix (P = 0.0199);Gain of helix (P = 0.0199);Gain of helix (P = 0.0199);
MVP		0.94
MPC		2.3
ClinPred		0.98	D
GERP RS		0.57
Varity_R		0.63
gMVP		0.98
Mutation Taster		=20/80	disease causing

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: rs768768744; hg19: chr19-13445220;