rs200633920

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PP3_Moderate

The NM_213599.3(ANO5):​c.1363C>T​(p.Arg455Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000112 in 1,612,338 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R455H) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000012 ( 0 hom. )

Consequence

ANO5
NM_213599.3 missense

Scores

2
9
8

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 3.05

Publications

0 publications found
Variant links:
Genes affected
ANO5 (HGNC:27337): (anoctamin 5) This gene encodes a member of the anoctamin family of transmembrane proteins. The encoded protein is likely a calcium activated chloride channel. Mutations in this gene have been associated with gnathodiaphyseal dysplasia. Alternatively spliced transcript variants have been described. [provided by RefSeq, Nov 2009]
ANO5 Gene-Disease associations (from GenCC):
  • autosomal recessive limb-girdle muscular dystrophy
    Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
  • gnathodiaphyseal dysplasia
    Inheritance: AD Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), G2P
  • autosomal recessive limb-girdle muscular dystrophy type 2L
    Inheritance: AR Classification: STRONG, SUPPORTIVE, LIMITED Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), G2P
  • Miyoshi muscular dystrophy 3
    Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PP3
MetaRNN computational evidence supports a deleterious effect, 0.898

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
ANO5NM_213599.3 linkc.1363C>T p.Arg455Cys missense_variant Exon 14 of 22 ENST00000324559.9 NP_998764.1 Q75V66

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
ANO5ENST00000324559.9 linkc.1363C>T p.Arg455Cys missense_variant Exon 14 of 22 1 NM_213599.3 ENSP00000315371.9 Q75V66

Frequencies

GnomAD3 genomes
AF:
0.00000658
AC:
1
AN:
152052
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.000207
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD2 exomes
AF:
0.00000398
AC:
1
AN:
251174
AF XY:
0.00000737
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00000881
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000116
AC:
17
AN:
1460286
Hom.:
0
Cov.:
30
AF XY:
0.0000124
AC XY:
9
AN XY:
726558
show subpopulations
African (AFR)
AF:
0.0000299
AC:
1
AN:
33442
American (AMR)
AF:
0.00
AC:
0
AN:
44706
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
26110
East Asian (EAS)
AF:
0.0000505
AC:
2
AN:
39638
South Asian (SAS)
AF:
0.00
AC:
0
AN:
86212
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
53364
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5764
European-Non Finnish (NFE)
AF:
0.0000126
AC:
14
AN:
1110722
Other (OTH)
AF:
0.00
AC:
0
AN:
60328
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.469
Heterozygous variant carriers
0
1
2
4
5
6
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:
0.00000658
AC:
1
AN:
152052
Hom.:
0
Cov.:
32
AF XY:
0.0000135
AC XY:
1
AN XY:
74274
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
41402
American (AMR)
AF:
0.00
AC:
0
AN:
15252
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
3468
East Asian (EAS)
AF:
0.00
AC:
0
AN:
5192
South Asian (SAS)
AF:
0.000207
AC:
1
AN:
4824
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
10582
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
316
European-Non Finnish (NFE)
AF:
0.00
AC:
0
AN:
68016
Other (OTH)
AF:
0.00
AC:
0
AN:
2088
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.575
Heterozygous variant carriers
0
0
1
1
2
2
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Genome 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
Alfa
AF:
0.0000282
Hom.:
0
Bravo
AF:
0.00000756
ExAC
AF:
0.00000824
AC:
1
Asia WGS
AF:
0.000866
AC:
3
AN:
3478
EpiCase
AF:
0.0000545
EpiControl
AF:
0.0000593

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Inborn genetic diseases Uncertain:1
Aug 14, 2024
Ambry Genetics
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

The c.1363C>T (p.R455C) alteration is located in exon 14 (coding exon 14) of the ANO5 gene. This alteration results from a C to T substitution at nucleotide position 1363, causing the arginine (R) at amino acid position 455 to be replaced by a cysteine (C). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Gnathodiaphyseal dysplasia;C1969785:Autosomal recessive limb-girdle muscular dystrophy type 2L Uncertain:1
Jun 04, 2022
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

ClinVar contains an entry for this variant (Variation ID: 578034). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt ANO5 protein function. This variant has not been reported in the literature in individuals affected with ANO5-related conditions. This variant is present in population databases (rs200633920, gnomAD 0.0009%). This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 455 of the ANO5 protein (p.Arg455Cys). -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.25
BayesDel_addAF
Uncertain
0.028
T
BayesDel_noAF
Benign
-0.20
CADD
Uncertain
24
DANN
Uncertain
1.0
DEOGEN2
Uncertain
0.57
D
Eigen
Uncertain
0.31
Eigen_PC
Uncertain
0.23
FATHMM_MKL
Uncertain
0.95
D
LIST_S2
Uncertain
0.87
D
M_CAP
Uncertain
0.10
D
MetaRNN
Pathogenic
0.90
D
MetaSVM
Benign
-0.32
T
MutationAssessor
Pathogenic
3.3
M
PhyloP100
3.0
PrimateAI
Benign
0.27
T
PROVEAN
Benign
-2.2
N
REVEL
Uncertain
0.37
Sift
Benign
0.030
D
Sift4G
Benign
0.064
T
Polyphen
0.99
D
Vest4
0.60
MutPred
0.66
Loss of MoRF binding (P = 0.1078);
MVP
0.66
MPC
0.44
ClinPred
0.92
D
GERP RS
5.7
Varity_R
0.12
gMVP
0.77
Mutation Taster
=76/24
polymorphism

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.080
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: rs200633920; hg19: chr11-22279256; COSMIC: COSV100201856; COSMIC: COSV100201856; API