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rs146341538

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM1BP4BS2

The NM_213599.3(ANO5):c.1924C>G(p.Arg642Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000539 in 1,613,926 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R642L) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000053 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000054 ( 0 hom. )

Consequence

ANO5
NM_213599.3 missense

Scores

4
9
6

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:7B:1

Conservation

PhyloP100: 1.39
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -3 ACMG points.

PM1
In a topological_domain Extracellular (size 100) in uniprot entity ANO5_HUMAN there are 14 pathogenic changes around while only 0 benign (100%) in NM_213599.3
BP4
Computational evidence support a benign effect (MetaRNN=0.37284726).
BS2
High AC in GnomAd at 8 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
ANO5NM_213599.3 linkuse as main transcriptc.1924C>G p.Arg642Gly missense_variant 18/22 ENST00000324559.9

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
ANO5ENST00000324559.9 linkuse as main transcriptc.1924C>G p.Arg642Gly missense_variant 18/221 NM_213599.3 P2

Frequencies

GnomAD3 genomes
AF:
0.0000526
AC:
8
AN:
152092
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00173
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000294
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.000107
AC:
27
AN:
251416
Hom.:
0
AF XY:
0.0000957
AC XY:
13
AN XY:
135880
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00238
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000176
Gnomad OTH exome
AF:
0.000163
GnomAD4 exome
AF:
0.0000540
AC:
79
AN:
1461834
Hom.:
0
Cov.:
31
AF XY:
0.0000578
AC XY:
42
AN XY:
727212
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00222
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.0000187
Gnomad4 NFE exome
AF:
0.00000899
Gnomad4 OTH exome
AF:
0.000166
GnomAD4 genome
AF:
0.0000526
AC:
8
AN:
152092
Hom.:
0
Cov.:
32
AF XY:
0.0000404
AC XY:
3
AN XY:
74256
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00173
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000294
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.000293
Hom.:
0
Bravo
AF:
0.0000831
ESP6500AA
AF:
0.00
AC:
0
ESP6500EA
AF:
0.000116
AC:
1
ExAC
AF:
0.000107
AC:
13
EpiCase
AF:
0.0000545
EpiControl
AF:
0.00

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:7Benign:1
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

not provided Uncertain:4
Uncertain significance, criteria provided, single submitterclinical testingRevvity Omics, RevvityOct 30, 2023- -
Uncertain significance, criteria provided, single submitterclinical testingCeGaT Center for Human Genetics TuebingenFeb 01, 2024ANO5: PM2 -
Uncertain significance, criteria provided, single submitterclinical testingGeneDxApr 04, 2019In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Has not been previously published as pathogenic or benign to our knowledge -
Uncertain significance, criteria provided, single submitterclinical testingEurofins Ntd Llc (ga)Apr 23, 2018- -
Limb-Girdle Muscular Dystrophy, Recessive Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaJun 14, 2016- -
ANO5-Related Muscle Diseases Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaJan 13, 2018This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -
Miyoshi myopathy Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaJun 14, 2016- -
Gnathodiaphyseal dysplasia;C1969785:Autosomal recessive limb-girdle muscular dystrophy type 2L Benign:1
Likely benign, criteria provided, single submitterclinical testingInvitaeDec 27, 2023- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.76
BayesDel_addAF
Pathogenic
0.24
D
BayesDel_noAF
Uncertain
0.12
Cadd
Uncertain
24
Dann
Uncertain
1.0
DEOGEN2
Benign
0.31
T
Eigen
Uncertain
0.56
Eigen_PC
Uncertain
0.54
FATHMM_MKL
Uncertain
0.88
D
LIST_S2
Uncertain
0.97
D
M_CAP
Benign
0.057
D
MetaRNN
Benign
0.37
T
MetaSVM
Benign
-0.30
T
MutationAssessor
Pathogenic
3.0
M
MutationTaster
Benign
1.0
D
PrimateAI
Uncertain
0.52
T
PROVEAN
Pathogenic
-5.5
D
REVEL
Uncertain
0.41
Sift
Uncertain
0.023
D
Sift4G
Benign
0.30
T
Polyphen
0.91
P
Vest4
0.72
MVP
0.77
MPC
0.40
ClinPred
0.87
D
GERP RS
5.7
Varity_R
0.70
gMVP
0.91

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

LitVar

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

Other links and lift over

dbSNP: rs146341538; hg19: chr11-22291883; API