NM_001127222.2:c.6659C>T

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4BS2

The NM_001127222.2(CACNA1A):​c.6659C>T​(p.Pro2220Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000616 in 1,459,922 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign 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. P2220H) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 31)
Exomes 𝑓: 0.0000061 ( 0 hom. )

Consequence

CACNA1A
NM_001127222.2 missense

Scores

2
4
13

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.81

Publications

1 publications found
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 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

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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

BP4
Computational evidence support a benign effect (MetaRNN=0.31727397).
BS2
High AC in GnomAdExome4 at 8 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
CACNA1ANM_001127222.2 linkc.6659C>T p.Pro2220Leu missense_variant Exon 46 of 47 ENST00000360228.11 NP_001120694.1 O00555-8

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
CACNA1AENST00000360228.11 linkc.6659C>T p.Pro2220Leu missense_variant Exon 46 of 47 1 NM_001127222.2 ENSP00000353362.5 O00555-8
CACNA1AENST00000638029.1 linkc.6677C>T p.Pro2226Leu missense_variant Exon 47 of 48 5 ENSP00000489829.1 A0A087WW63
CACNA1AENST00000573710.7 linkc.6665C>T p.Pro2222Leu missense_variant Exon 46 of 47 5 ENSP00000460092.3 A0A1C7CYY9
CACNA1AENST00000635727.1 linkc.6662C>T p.Pro2221Leu missense_variant Exon 46 of 47 5 ENSP00000490001.1 A0A1B0GU81
CACNA1AENST00000637769.1 linkc.6662C>T p.Pro2221Leu missense_variant Exon 46 of 47 1 ENSP00000489778.1 A0A1B0GTN7
CACNA1AENST00000636012.1 linkc.6626C>T p.Pro2209Leu missense_variant Exon 45 of 46 5 ENSP00000490223.1 A0A1B0GUS3
CACNA1AENST00000637736.1 linkc.6521C>T p.Pro2174Leu missense_variant Exon 45 of 46 5 ENSP00000489861.1 A0A1B0GTW2
CACNA1AENST00000636389.1 linkc.6662C>T p.Pro2221Leu missense_variant Exon 46 of 47 5 ENSP00000489992.1 A0A1B0GU74
CACNA1AENST00000637432.1 linkc.6677C>T p.Pro2226Leu missense_variant Exon 47 of 48 5 ENSP00000490617.1 O00555-2
CACNA1AENST00000636549.1 linkc.6668C>T p.Pro2223Leu missense_variant Exon 47 of 48 5 ENSP00000490578.1 B5TYJ1
CACNA1AENST00000637927.1 linkc.6665C>T p.Pro2222Leu missense_variant Exon 46 of 47 5 ENSP00000489715.1 A0A1B0GTI4
CACNA1AENST00000635895.1 linkc.6662C>T p.Pro2221Leu missense_variant Exon 46 of 47 5 ENSP00000490323.1 A0A384DVW2
CACNA1AENST00000638009.2 linkc.6662C>T p.Pro2221Leu missense_variant Exon 46 of 47 1 ENSP00000489913.1 O00555-3
CACNA1AENST00000637276.1 linkc.6626C>T p.Pro2209Leu missense_variant Exon 45 of 46 5 ENSP00000489777.1 O00555-5
CACNA1AENST00000636768.2 linkn.*925C>T non_coding_transcript_exon_variant Exon 44 of 45 5 ENSP00000490190.2 A0A1B0GUP3
CACNA1AENST00000713789.1 linkn.*1838C>T non_coding_transcript_exon_variant Exon 46 of 47 ENSP00000519091.1
CACNA1AENST00000636768.2 linkn.*925C>T 3_prime_UTR_variant Exon 44 of 45 5 ENSP00000490190.2 A0A1B0GUP3
CACNA1AENST00000713789.1 linkn.*1838C>T 3_prime_UTR_variant Exon 46 of 47 ENSP00000519091.1

Frequencies

GnomAD3 genomes
AF:
0.00000665
AC:
1
AN:
150462
Hom.:
0
Cov.:
31
show subpopulations
Gnomad AFR
AF:
0.0000245
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
GnomAD4 exome
AF:
0.00000611
AC:
8
AN:
1309460
Hom.:
0
Cov.:
76
AF XY:
0.00000773
AC XY:
5
AN XY:
646842
show subpopulations
African (AFR)
AF:
0.0000345
AC:
1
AN:
28996
American (AMR)
AF:
0.00
AC:
0
AN:
33894
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
24028
East Asian (EAS)
AF:
0.00
AC:
0
AN:
32968
South Asian (SAS)
AF:
0.00
AC:
0
AN:
76342
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
32216
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5258
European-Non Finnish (NFE)
AF:
0.00000686
AC:
7
AN:
1021002
Other (OTH)
AF:
0.00
AC:
0
AN:
54756
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.481
Heterozygous variant carriers
0
1
2
2
3
4
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Variant carriers
0
2
4
6
8
10
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
GnomAD4 genome
AF:
0.00000665
AC:
1
AN:
150462
Hom.:
0
Cov.:
31
AF XY:
0.0000136
AC XY:
1
AN XY:
73422
show subpopulations
⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.
African (AFR)
AF:
0.0000245
AC:
1
AN:
40868
American (AMR)
AF:
0.00
AC:
0
AN:
15138
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
3460
East Asian (EAS)
AF:
0.00
AC:
0
AN:
5018
South Asian (SAS)
AF:
0.00
AC:
0
AN:
4740
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
10434
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
314
European-Non Finnish (NFE)
AF:
0.00
AC:
0
AN:
67518
Other (OTH)
AF:
0.00
AC:
0
AN:
2068
⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.275
Heterozygous variant carriers
0
0
1
1
2
2
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
Alfa
AF:
0.00
Hom.:
0
Bravo
AF:
0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.099
BayesDel_addAF
Uncertain
0.11
D
BayesDel_noAF
Uncertain
-0.070
CADD
Benign
20
DANN
Benign
0.97
DEOGEN2
Benign
0.0096
.;.;T;.;.;.;.;.;T;.;.;T;.;.;.;T;.;.
Eigen
Benign
-0.43
Eigen_PC
Benign
-0.28
FATHMM_MKL
Benign
0.49
N
LIST_S2
Uncertain
0.94
D;D;D;D;D;T;D;D;D;D;.;D;D;D;D;D;D;D
M_CAP
Pathogenic
0.82
D
MetaRNN
Benign
0.32
T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM
Uncertain
0.13
D
MutationAssessor
Benign
0.14
.;.;.;.;N;.;.;.;.;.;.;.;.;.;.;.;.;.
PhyloP100
1.8
PrimateAI
Pathogenic
0.87
D
PROVEAN
Benign
-1.1
.;N;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.
REVEL
Benign
0.26
Sift
Benign
0.048
.;D;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.
Sift4G
Benign
0.17
T;T;.;.;.;T;.;.;.;.;.;.;.;.;.;.;.;.
Vest4
0.32
MutPred
0.28
.;.;Loss of relative solvent accessibility (P = 0.0404);Loss of relative solvent accessibility (P = 0.0404);Loss of relative solvent accessibility (P = 0.0404);.;.;Loss of relative solvent accessibility (P = 0.0404);.;.;.;.;Loss of relative solvent accessibility (P = 0.0404);.;.;.;.;.;
MVP
0.83
MPC
0.83
ClinPred
0.61
D
GERP RS
2.7
Varity_R
0.053
gMVP
0.16
Mutation Taster
=75/25
polymorphism

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.020
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

Other links and lift over

dbSNP: rs16052; hg19: chr19-13319691; API