19-13365344-G-C

Variant names:

• chr19-13365344-G-C
• rs121908228
• NM_001127222.2:c.757C>G

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PM1 PM2 PM5 PP3_Moderate

The NM_001127222.2(CACNA1A):​c.757C>G​(p.His253Asp) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 13/22 in silico tools predict a damaging 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. H253Y) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: CACNA1A NM_001127222.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 9.88
• 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_pathogenic. The variant received 8 ACMG points.

• PM1: In a topological_domain Extracellular (size 86) in uniprot entity CAC1A_HUMAN there are 15 pathogenic changes around while only 1 benign (94%) in NM_001127222.2
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr19-13365344-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 68442.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.921

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1A	NM_001127222.2	c.757C>G	p.His253Asp	missense_variant	Exon 5 of 47	ENST00000360228.11	NP_001120694.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CACNA1A	ENST00000360228.11	c.757C>G	p.His253Asp	missense_variant	Exon 5 of 47	1	NM_001127222.2	ENSP00000353362.5
CACNA1A	ENST00000638029.1	c.757C>G	p.His253Asp	missense_variant	Exon 5 of 48	5		ENSP00000489829.1
CACNA1A	ENST00000573710.7	c.757C>G	p.His253Asp	missense_variant	Exon 5 of 47	5		ENSP00000460092.3
CACNA1A	ENST00000635727.1	c.757C>G	p.His253Asp	missense_variant	Exon 5 of 47	5		ENSP00000490001.1
CACNA1A	ENST00000637769.1	c.757C>G	p.His253Asp	missense_variant	Exon 5 of 47	1		ENSP00000489778.1
CACNA1A	ENST00000636012.1	c.757C>G	p.His253Asp	missense_variant	Exon 5 of 46	5		ENSP00000490223.1
CACNA1A	ENST00000637736.1	c.616C>G	p.His206Asp	missense_variant	Exon 4 of 46	5		ENSP00000489861.1
CACNA1A	ENST00000636389.1	c.757C>G	p.His253Asp	missense_variant	Exon 5 of 47	5		ENSP00000489992.1
CACNA1A	ENST00000637432.1	c.757C>G	p.His253Asp	missense_variant	Exon 5 of 48	5		ENSP00000490617.1
CACNA1A	ENST00000636549.1	c.757C>G	p.His253Asp	missense_variant	Exon 5 of 48	5		ENSP00000490578.1
CACNA1A	ENST00000637927.1	c.757C>G	p.His253Asp	missense_variant	Exon 5 of 47	5		ENSP00000489715.1
CACNA1A	ENST00000635895.1	c.757C>G	p.His253Asp	missense_variant	Exon 5 of 47	5		ENSP00000490323.1
CACNA1A	ENST00000638009.2	c.757C>G	p.His253Asp	missense_variant	Exon 5 of 47	1		ENSP00000489913.1
CACNA1A	ENST00000637276.1	c.757C>G	p.His253Asp	missense_variant	Exon 5 of 46	5		ENSP00000489777.1
CACNA1A	ENST00000636768.2	n.757C>G		non_coding_transcript_exon_variant	Exon 5 of 45	5		ENSP00000490190.2
CACNA1A	ENST00000713789.1	n.757C>G		non_coding_transcript_exon_variant	Exon 5 of 47			ENSP00000519091.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.53	D
BayesDel_noAF	Pathogenic	0.52
CADD	Pathogenic	31
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.95	.;D;T;.;.;.;.;.;.;T;.;.;.;T;.
Eigen	Pathogenic	0.93
Eigen_PC	Pathogenic	0.91
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	D;D;D;D;D;D;D;D;.;D;D;D;D;D;D
M_CAP	Pathogenic	0.72	D
MetaRNN	Pathogenic	0.92	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.1	.;M;.;.;M;.;.;M;.;.;.;.;M;.;.
PhyloP100		9.9
PrimateAI	Pathogenic	0.82	D
PROVEAN	Pathogenic	-7.5	.;D;.;.;.;.;.;.;.;.;.;.;.;.;.
REVEL	Pathogenic	0.97
Sift	Uncertain	0.013	.;D;.;.;.;.;.;.;.;.;.;.;.;.;.
Sift4G	Uncertain	0.0020	D;D;.;.;.;.;.;.;.;.;.;D;.;.;.
Polyphen		1.0	.;D;.;.;.;.;.;.;.;.;.;.;.;.;.
Vest4		0.80
MutPred		0.60		Gain of helix (P = 0.027);Gain of helix (P = 0.027);Gain of helix (P = 0.027);Gain of helix (P = 0.027);Gain of helix (P = 0.027);.;Gain of helix (P = 0.027);Gain of helix (P = 0.027);Gain of helix (P = 0.027);Gain of helix (P = 0.027);Gain of helix (P = 0.027);Gain of helix (P = 0.027);Gain of helix (P = 0.027);Gain of helix (P = 0.027);Gain of helix (P = 0.027);
MVP		0.95
MPC		2.3
ClinPred		1.0	D
GERP RS		5.5
Varity_R		0.92
gMVP		1.0
Mutation Taster		=6/94	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: rs121908228; hg19: chr19-13476158;