NM_001127222.2:c.2173-12C>T

Variant names:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001127222.2(CACNA1A):c.2173-12C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.715 in 1,608,152 control chromosomes in the GnomAD database, including 416,334 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.67 ( 35710 hom., cov: 31)

Exomes 𝑓: 0.72 ( 380624 hom. )

Consequence

CACNA1A
NM_001127222.2 intron

Scores

Splicing: ADA: 0.00002687

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:13

Conservation

PhyloP100: 0.528

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.87).

BP6

Variant 19-13300668-G-A is Benign according to our data. Variant chr19-13300668-G-A is described in ClinVar as [Benign]. Clinvar id is 257510.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-13300668-G-A is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.974 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1A	NM_001127222.2 link	c.2173-12C>T		intron_variant	Intron 17 of 46	ENST00000360228.11	NP_001120694.1	O00555-8

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein	UniProt
CACNA1A	ENST00000360228.11 link	c.2173-12C>T	intron_variant	Intron 17 of 46	1	NM_001127222.2	ENSP00000353362.5	O00555-8
CACNA1A	ENST00000638029.1 link	c.2185-12C>T	intron_variant	Intron 17 of 47	5		ENSP00000489829.1	A0A087WW63
CACNA1A	ENST00000573710.7 link	c.2179-12C>T	intron_variant	Intron 17 of 46	5		ENSP00000460092.3	A0A1C7CYY9
CACNA1A	ENST00000635727.1 link	c.2176-12C>T	intron_variant	Intron 17 of 46	5		ENSP00000490001.1	A0A1B0GU81
CACNA1A	ENST00000637769.1 link	c.2176-12C>T	intron_variant	Intron 17 of 46	1		ENSP00000489778.1	A0A1B0GTN7
CACNA1A	ENST00000636012.1 link	c.2176-12C>T	intron_variant	Intron 17 of 45	5		ENSP00000490223.1	A0A1B0GUS3
CACNA1A	ENST00000637736.1 link	c.2035-12C>T	intron_variant	Intron 16 of 45	5		ENSP00000489861.1	A0A1B0GTW2
CACNA1A	ENST00000636389.1 link	c.2176-12C>T	intron_variant	Intron 17 of 46	5		ENSP00000489992.1	A0A1B0GU74
CACNA1A	ENST00000637432.1 link	c.2185-12C>T	intron_variant	Intron 17 of 47	5		ENSP00000490617.1	O00555-2
CACNA1A	ENST00000636549.1 link	c.2176-12C>T	intron_variant	Intron 17 of 47	5		ENSP00000490578.1	B5TYJ1
CACNA1A	ENST00000637927.1 link	c.2179-12C>T	intron_variant	Intron 17 of 46	5		ENSP00000489715.1	A0A1B0GTI4
CACNA1A	ENST00000635895.1 link	c.2176-12C>T	intron_variant	Intron 17 of 46	5		ENSP00000490323.1	A0A384DVW2
CACNA1A	ENST00000638009.2 link	c.2176-12C>T	intron_variant	Intron 17 of 46	1		ENSP00000489913.1	O00555-3
CACNA1A	ENST00000637276.1 link	c.2176-12C>T	intron_variant	Intron 17 of 45	5		ENSP00000489777.1	O00555-5

Frequencies

GnomAD3 genomes

AF:

0.674

AC:

102301

AN:

151828

Hom.:

35690

Cov.:

show subpopulations

Gnomad AFR

AF:

0.500

Gnomad AMI

AF:

0.700

Gnomad AMR

AF:

0.759

Gnomad ASJ

AF:

0.693

Gnomad EAS

AF:

0.996

Gnomad SAS

AF:

0.853

Gnomad FIN

AF:

0.793

Gnomad MID

AF:

0.658

Gnomad NFE

AF:

0.703

Gnomad OTH

AF:

0.680

GnomAD3 exomes

AF:

0.755

AC:

188197

AN:

249270

Hom.:

72716

AF XY:

0.757

AC XY:

102313

AN XY:

135238

show subpopulations

Gnomad AFR exome

AF:

0.499

Gnomad AMR exome

AF:

0.840

Gnomad ASJ exome

AF:

0.700

Gnomad EAS exome

AF:

0.998

Gnomad SAS exome

AF:

0.842

Gnomad FIN exome

AF:

0.785

Gnomad NFE exome

AF:

0.703

Gnomad OTH exome

AF:

0.726

GnomAD4 exome

AF:

0.719

AC:

1046691

AN:

1456206

Hom.:

380624

Cov.:

AF XY:

0.723

AC XY:

523830

AN XY:

724794

show subpopulations

Gnomad4 AFR exome

AF:

0.496

Gnomad4 AMR exome

AF:

0.832

Gnomad4 ASJ exome

AF:

0.704

Gnomad4 EAS exome

AF:

0.991

Gnomad4 SAS exome

AF:

0.839

Gnomad4 FIN exome

AF:

0.780

Gnomad4 NFE exome

AF:

0.700

Gnomad4 OTH exome

AF:

0.718

GnomAD4 genome

AF:

0.674

AC:

102368

AN:

151946

Hom.:

35710

Cov.:

AF XY:

0.683

AC XY:

50750

AN XY:

74258

show subpopulations

Gnomad4 AFR

AF:

0.500

Gnomad4 AMR

AF:

0.760

Gnomad4 ASJ

AF:

0.693

Gnomad4 EAS

AF:

0.996

Gnomad4 SAS

AF:

0.852

Gnomad4 FIN

AF:

0.793

Gnomad4 NFE

AF:

0.703

Gnomad4 OTH

AF:

0.684

Alfa

AF:

0.701

Hom.:

58741

Bravo

AF:

0.662

Asia WGS

AF:

0.898

AC:

3121

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:13

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:7

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jul 15, 2024

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is classified as Benign based on local population frequency. This variant was detected in 98% of patients studied in a panel designed for Epileptic and Developmental Encephalopathy and Progressive Myoclonus Epilepsy. Number of patients: 91. Only high quality variants are reported. -

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jan 07, 2016

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Spinocerebellar ataxia type 6

Benign:1

Jul 14, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Episodic ataxia type 2

Benign:1

Jul 14, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

Benign:1

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided

Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Migraine, familial hemiplegic, 1

Benign:1

Jul 14, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Developmental and epileptic encephalopathy, 42

Benign:1

Jul 14, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.87

CADD

Benign

3.6

DANN

Benign

0.66

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000027

dbscSNV1_RF

Benign

0.0060

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over