NM_001127222.2:c.7436C>G

Variant names:

• chr19-13207398-G-C
• rs758817759
• NM_001127222.2:c.7436C>G

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4 BS2

The NM_001127222.2(CACNA1A):​c.7436C>G​(p.Ala2479Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000455 in 1,538,216 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000033 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: CACNA1A NM_001127222.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.67
• 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

ENSG00000300728 (HGNC:):

ACMG classification

Our verdict: Likely_benign. The variant received -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.26487607).
• BS2: High AC in GnomAd4 at 5 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1A	NM_001127222.2	c.7436C>G	p.Ala2479Gly	missense_variant	Exon 47 of 47	ENST00000360228.11	NP_001120694.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CACNA1A	ENST00000360228.11	c.7436C>G	p.Ala2479Gly	missense_variant	Exon 47 of 47	1	NM_001127222.2	ENSP00000353362.5
CACNA1A	ENST00000638029.1	c.7454C>G	p.Ala2485Gly	missense_variant	Exon 48 of 48	5		ENSP00000489829.1
CACNA1A	ENST00000573710.7	c.7442C>G	p.Ala2481Gly	missense_variant	Exon 47 of 47	5		ENSP00000460092.3
CACNA1A	ENST00000635727.1	c.7439C>G	p.Ala2480Gly	missense_variant	Exon 47 of 47	5		ENSP00000490001.1
CACNA1A	ENST00000637769.1	c.7439C>G	p.Ala2480Gly	missense_variant	Exon 47 of 47	1		ENSP00000489778.1
CACNA1A	ENST00000636012.1	c.7403C>G	p.Ala2468Gly	missense_variant	Exon 46 of 46	5		ENSP00000490223.1
CACNA1A	ENST00000637736.1	c.7298C>G	p.Ala2433Gly	missense_variant	Exon 46 of 46	5		ENSP00000489861.1
CACNA1A	ENST00000636768.2	n.*1697C>G		non_coding_transcript_exon_variant	Exon 45 of 45	5		ENSP00000490190.2
CACNA1A	ENST00000713789.1	n.*2615C>G		non_coding_transcript_exon_variant	Exon 47 of 47			ENSP00000519091.1
CACNA1A	ENST00000636389.1	c.*522C>G		3_prime_UTR_variant	Exon 47 of 47	5		ENSP00000489992.1
CACNA1A	ENST00000637432.1	c.*648C>G		3_prime_UTR_variant	Exon 48 of 48	5		ENSP00000490617.1
CACNA1A	ENST00000635895.1	c.*648C>G		3_prime_UTR_variant	Exon 47 of 47	5		ENSP00000490323.1
CACNA1A	ENST00000638009.2	c.*648C>G		3_prime_UTR_variant	Exon 47 of 47	1		ENSP00000489913.1
CACNA1A	ENST00000636768.2	n.*1697C>G		3_prime_UTR_variant	Exon 45 of 45	5		ENSP00000490190.2
CACNA1A	ENST00000713789.1	n.*2615C>G		3_prime_UTR_variant	Exon 47 of 47			ENSP00000519091.1

Frequencies

GnomAD3 genomes AF: 0.0000329 AC: 5 AN: 151752 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.000121

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

GnomAD2 exomes AF: 0.00000710 AC: 1 AN: 140814 AF XY: 0.0000128

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: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000144 AC: 2 AN: 1386464 Hom.: 0 Cov.: 30 AF XY: 0.00000146 AC XY: 1 AN XY: 686126

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0000644 AC: 2 AN: 31052

American (AMR) AF: 0.00 AC: 0 AN: 36624

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24836

East Asian (EAS) AF: 0.00 AC: 0 AN: 35670

South Asian (SAS) AF: 0.00 AC: 0 AN: 80186

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 34598

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5650

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1080218

Other (OTH) AF: 0.00 AC: 0 AN: 57630

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.0000329 AC: 5 AN: 151752 Hom.: 0 Cov.: 31 AF XY: 0.0000270 AC XY: 2 AN XY: 74144

African (AFR) AF: 0.000121 AC: 5 AN: 41360

American (AMR) AF: 0.00 AC: 0 AN: 15244

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5164

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10518

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67862

Other (OTH) AF: 0.00 AC: 0 AN: 2086

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.0000264

ExAC AF: 0.00000959 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Sep 18, 2017

Athena Diagnostics

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	Benign	0.082
BayesDel_addAF	Benign	-0.026	T
BayesDel_noAF	Benign	-0.15
CADD	Benign	16
DANN	Benign	0.85
DEOGEN2	Benign	0.023	.;.;T;.;.;T;.;T;.;.
Eigen	Benign	-0.67
Eigen_PC	Benign	-0.54
FATHMM_MKL	Benign	0.29	N
LIST_S2	Benign	0.69	T;T;T;T;T;T;.;T;T;T
M_CAP	Pathogenic	0.97	D
MetaRNN	Benign	0.26	T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.41	T
PhyloP100		1.7
PrimateAI	Pathogenic	0.90	D
PROVEAN	Benign	-0.88	.;N;.;.;.;.;.;.;.;.
REVEL	Uncertain	0.35
Sift	Benign	0.20	.;T;.;.;.;.;.;.;.;.
Sift4G	Benign	0.19	T;T;.;T;.;.;.;.;.;.
Vest4		0.048
MutPred		0.20		.;Gain of catalytic residue at A2479 (P = 0.0817);.;.;.;.;.;.;.;.;
MVP		0.73
MPC		0.71
ClinPred		0.21	T
GERP RS		0.25
Varity_R		0.065
gMVP		0.20
Mutation Taster		=89/11	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: rs758817759; hg19: chr19-13318212;