19-13212196-C-G

Variant names:

• chr19-13212196-C-G
• rs1555731738
• NM_001127222.2:c.6210G>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001127222.2(CACNA1A):​c.6210G>C​(p.Met2070Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,534 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M2070T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: CACNA1A NM_001127222.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.08
• 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.13790739).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1A	NM_001127222.2	c.6210G>C	p.Met2070Ile	missense_variant	Exon 43 of 47	ENST00000360228.11	NP_001120694.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CACNA1A	ENST00000360228.11	c.6210G>C	p.Met2070Ile	missense_variant	Exon 43 of 47	1	NM_001127222.2	ENSP00000353362.5
CACNA1A	ENST00000638029.1	c.6228G>C	p.Met2076Ile	missense_variant	Exon 44 of 48	5		ENSP00000489829.1
CACNA1A	ENST00000573710.7	c.6216G>C	p.Met2072Ile	missense_variant	Exon 43 of 47	5		ENSP00000460092.3
CACNA1A	ENST00000635727.1	c.6213G>C	p.Met2071Ile	missense_variant	Exon 43 of 47	5		ENSP00000490001.1
CACNA1A	ENST00000637769.1	c.6213G>C	p.Met2071Ile	missense_variant	Exon 43 of 47	1		ENSP00000489778.1
CACNA1A	ENST00000636012.1	c.6213G>C	p.Met2071Ile	missense_variant	Exon 43 of 46	5		ENSP00000490223.1
CACNA1A	ENST00000637736.1	c.6072G>C	p.Met2024Ile	missense_variant	Exon 42 of 46	5		ENSP00000489861.1
CACNA1A	ENST00000636389.1	c.6213G>C	p.Met2071Ile	missense_variant	Exon 43 of 47	5		ENSP00000489992.1
CACNA1A	ENST00000637432.1	c.6228G>C	p.Met2076Ile	missense_variant	Exon 44 of 48	5		ENSP00000490617.1
CACNA1A	ENST00000636549.1	c.6219G>C	p.Met2073Ile	missense_variant	Exon 44 of 48	5		ENSP00000490578.1
CACNA1A	ENST00000637927.1	c.6216G>C	p.Met2072Ile	missense_variant	Exon 43 of 47	5		ENSP00000489715.1
CACNA1A	ENST00000635895.1	c.6213G>C	p.Met2071Ile	missense_variant	Exon 43 of 47	5		ENSP00000490323.1
CACNA1A	ENST00000638009.2	c.6213G>C	p.Met2071Ile	missense_variant	Exon 43 of 47	1		ENSP00000489913.1
CACNA1A	ENST00000637276.1	c.6213G>C	p.Met2071Ile	missense_variant	Exon 43 of 46	5		ENSP00000489777.1
CACNA1A	ENST00000636768.2	n.*512G>C		non_coding_transcript_exon_variant	Exon 42 of 45	5		ENSP00000490190.2
CACNA1A	ENST00000713789.1	n.*1425G>C		non_coding_transcript_exon_variant	Exon 44 of 47			ENSP00000519091.1
CACNA1A	ENST00000636768.2	n.*512G>C		3_prime_UTR_variant	Exon 42 of 45	5		ENSP00000490190.2
CACNA1A	ENST00000713789.1	n.*1425G>C		3_prime_UTR_variant	Exon 44 of 47			ENSP00000519091.1

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461534 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 727080

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44712

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.00 AC: 0 AN: 86248

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53386

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111750

Other (OTH) AF: 0.00 AC: 0 AN: 60364

GnomAD4 genome Cov.: 34

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.30
BayesDel_addAF	Uncertain	0.030	T
BayesDel_noAF	Benign	-0.19
CADD	Benign	20
DANN	Benign	0.93
DEOGEN2	Benign	0.031	.;.;T;.;.;.;.;.;T;.;.;T;.;.;.;T;.;.
Eigen	Benign	-0.75
Eigen_PC	Benign	-0.67
FATHMM_MKL	Uncertain	0.79	D
LIST_S2	Uncertain	0.87	D;D;D;D;D;D;D;D;D;D;.;D;D;D;D;D;D;D
M_CAP	Benign	0.040	D
MetaRNN	Benign	0.14	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.88	T
MutationAssessor	Benign	1.6	.;.;.;.;L;.;.;.;.;.;.;.;.;.;L;.;.;.
PhyloP100		2.1
PrimateAI	Uncertain	0.56	T
PROVEAN	Uncertain	-2.7	.;D;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.
REVEL	Uncertain	0.35
Sift	Benign	0.31	.;T;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.
Sift4G	Benign	0.39	T;T;.;.;.;T;.;.;.;.;.;.;.;.;.;.;.;.
Vest4		0.41
MutPred		0.27		.;.;Loss of catalytic residue at M2071 (P = 0.2486);Loss of catalytic residue at M2071 (P = 0.2486);Loss of catalytic residue at M2071 (P = 0.2486);.;.;Loss of catalytic residue at M2071 (P = 0.2486);.;.;.;Loss of catalytic residue at M2071 (P = 0.2486);Loss of catalytic residue at M2071 (P = 0.2486);.;Loss of catalytic residue at M2071 (P = 0.2486);.;.;.;
MVP		0.79
MPC		0.32
ClinPred		0.18	T
GERP RS		2.3
Varity_R		0.17
gMVP		0.40
Mutation Taster		=84/16	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: rs1555731738; hg19: chr19-13323010; COSMIC: COSV64203736; COSMIC: COSV64203736;