19-13209324-C-G

Variant names:

• chr19-13209324-C-G
• NM_001127222.2:c.6514G>C

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP2

The NM_001127222.2(CACNA1A):​c.6514G>C​(p.Asp2172His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000024 in 1,248,106 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. D2172N) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000024 (0 hom.)
• Consequence: CACNA1A NM_001127222.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.42

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the CACNA1A gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 137 curated pathogenic missense variants (we use a threshold of 10). The gene has 132 curated benign missense variants. Gene score misZ: 5.7845 (above the threshold of 3.09). Trascript score misZ: 3.9354 (above the threshold of 3.09). GenCC associations: The gene is linked to benign paroxysmal torticollis of infancy, developmental and epileptic encephalopathy, 42, undetermined early-onset epileptic encephalopathy, episodic ataxia type 2, familial or sporadic hemiplegic migraine, spinocerebellar ataxia type 6, Lennox-Gastaut syndrome, migraine, familial hemiplegic, 1.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1A	NM_001127222.2	c.6514G>C	p.Asp2172His	missense_variant	Exon 45 of 47	ENST00000360228.11	NP_001120694.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CACNA1A	ENST00000360228.11	c.6514G>C	p.Asp2172His	missense_variant	Exon 45 of 47	1	NM_001127222.2	ENSP00000353362.5
CACNA1A	ENST00000638029.1	c.6532G>C	p.Asp2178His	missense_variant	Exon 46 of 48	5		ENSP00000489829.1
CACNA1A	ENST00000573710.7	c.6520G>C	p.Asp2174His	missense_variant	Exon 45 of 47	5		ENSP00000460092.3
CACNA1A	ENST00000635727.1	c.6517G>C	p.Asp2173His	missense_variant	Exon 45 of 47	5		ENSP00000490001.1
CACNA1A	ENST00000637769.1	c.6517G>C	p.Asp2173His	missense_variant	Exon 45 of 47	1		ENSP00000489778.1
CACNA1A	ENST00000636012.1	c.6481G>C	p.Asp2161His	missense_variant	Exon 44 of 46	5		ENSP00000490223.1
CACNA1A	ENST00000637736.1	c.6376G>C	p.Asp2126His	missense_variant	Exon 44 of 46	5		ENSP00000489861.1
CACNA1A	ENST00000636389.1	c.6517G>C	p.Asp2173His	missense_variant	Exon 45 of 47	5		ENSP00000489992.1
CACNA1A	ENST00000637432.1	c.6532G>C	p.Asp2178His	missense_variant	Exon 46 of 48	5		ENSP00000490617.1
CACNA1A	ENST00000636549.1	c.6523G>C	p.Asp2175His	missense_variant	Exon 46 of 48	5		ENSP00000490578.1
CACNA1A	ENST00000637927.1	c.6520G>C	p.Asp2174His	missense_variant	Exon 45 of 47	5		ENSP00000489715.1
CACNA1A	ENST00000635895.1	c.6517G>C	p.Asp2173His	missense_variant	Exon 45 of 47	5		ENSP00000490323.1
CACNA1A	ENST00000638009.2	c.6517G>C	p.Asp2173His	missense_variant	Exon 45 of 47	1		ENSP00000489913.1
CACNA1A	ENST00000637276.1	c.6481G>C	p.Asp2161His	missense_variant	Exon 44 of 46	5		ENSP00000489777.1
CACNA1A	ENST00000636768.1	n.*780G>C		non_coding_transcript_exon_variant	Exon 9 of 10	5		ENSP00000490190.2
CACNA1A	ENST00000636768.1	n.*780G>C		3_prime_UTR_variant	Exon 9 of 10	5		ENSP00000490190.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000240 AC: 3 AN: 1248106 Hom.: 0 Cov.: 32 AF XY: 0.00000166 AC XY: 1 AN XY: 601962

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000298

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.91
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Uncertain	0.010
CADD	Uncertain	24
DANN	Benign	0.87
DEOGEN2	Benign	0.058	.;.;T;.;.;.;.;.;T;.;.;T;.;.;.;T;.;.
Eigen	Benign	-0.19
Eigen_PC	Benign	-0.29
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Pathogenic	0.98	D;D;D;D;D;D;D;D;D;D;.;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.31	D
MetaRNN	Uncertain	0.71	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.21	D
MutationAssessor	Uncertain	2.5	.;.;.;.;M;.;.;.;.;.;.;.;.;.;.;.;.;.
PrimateAI	Pathogenic	0.87	D
PROVEAN	Uncertain	-3.8	.;D;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.
REVEL	Uncertain	0.43
Sift	Benign	0.033	.;D;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.
Sift4G	Benign	0.17	T;T;.;.;.;T;.;.;.;.;.;.;.;.;.;.;.;.
Vest4		0.60
MutPred		0.29		.;.;Gain of MoRF binding (P = 0.05);Gain of MoRF binding (P = 0.05);Gain of MoRF binding (P = 0.05);.;.;Gain of MoRF binding (P = 0.05);.;.;.;.;Gain of MoRF binding (P = 0.05);.;.;.;.;.;
MVP		0.90
MPC		0.45
ClinPred		0.98	D
GERP RS		1.3
Varity_R		0.26
gMVP		0.32

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr19-13320138;