rs142073798

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Pathogenic. The variant received 13 ACMG points: 13P and 0B. PM1PM5PP3PP5_Very_Strong

The NM_213599.3(ANO5):c.2498T>A(p.Met833Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000101 in 1,610,652 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 Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M833R) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.00013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000098 ( 0 hom. )

Consequence

ANO5
NM_213599.3 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:11

Conservation

PhyloP100: 7.95

Publications

3 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)

ANO5 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 13 ACMG points.

PM1

In a topological_domain Extracellular (size 80) in uniprot entity ANO5_HUMAN there are 6 pathogenic changes around while only 2 benign (75%) in NM_213599.3

PM5

Other missense variant is known to change same aminoacid residue: Variant chr11-22276177-T-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 2430738.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.809

PP5

Variant 11-22276177-T-A is Pathogenic according to our data. Variant chr11-22276177-T-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 285338.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ANO5	NM_213599.3 link	c.2498T>A	p.Met833Lys	missense_variant	Exon 21 of 22	ENST00000324559.9	NP_998764.1	Q75V66

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ANO5	ENST00000324559.9 link	c.2498T>A	p.Met833Lys	missense_variant	Exon 21 of 22	1	NM_213599.3	ENSP00000315371.9		Q75V66

Frequencies

GnomAD3 genomes

AF:

0.000132

AC:

AN:

151824

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000657

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:

0.000162

Gnomad OTH

AF:

0.000479

GnomAD2 exomes

AF:

0.000120

AC:

AN:

250750

AF XY:

0.000125

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00109

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000159

Gnomad OTH exome

AF:

0.000164

GnomAD4 exome

AF:

0.0000980

AC:

143

AN:

1458828

Hom.:

Cov.:

AF XY:

0.0000951

AC XY:

AN XY:

725810

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33368

American (AMR)

AF:

0.0000224

AC:

AN:

44618

Ashkenazi Jewish (ASJ)

AF:

0.00157

AC:

AN:

26056

East Asian (EAS)

AF:

0.00

AC:

AN:

39566

South Asian (SAS)

AF:

0.00

AC:

AN:

86174

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53368

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5756

European-Non Finnish (NFE)

AF:

0.0000829

AC:

AN:

1109678

Other (OTH)

AF:

0.000149

AC:

AN:

60244

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.467

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<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:

0.000132

AC:

AN:

151824

Hom.:

Cov.:

AF XY:

0.000135

AC XY:

AN XY:

74174

show subpopulations

African (AFR)

AF:

0.0000241

AC:

AN:

41428

American (AMR)

AF:

0.0000657

AC:

AN:

15226

Ashkenazi Jewish (ASJ)

AF:

0.00173

AC:

AN:

3464

East Asian (EAS)

AF:

0.00

AC:

AN:

5194

South Asian (SAS)

AF:

0.00

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10620

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.000162

AC:

AN:

67752

Other (OTH)

AF:

0.000479

AC:

AN:

2086

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.510

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.000224

Hom.:

Bravo

AF:

0.000113

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.000132

AC:

EpiCase

AF:

0.0000546

EpiControl

AF:

0.000119

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:5

Oct 23, 2020

Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 27, 2017

Eurofins Ntd Llc (ga)

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Nov 27, 2023

Athena Diagnostics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The frequency of this variant in the general population is consistent with pathogenicity. (http://gnomad.broadinstitute.org) This variant has been identified in multiple unrelated individuals with autosomal recessive limb-girdle muscular dystrophy. Computational tools predict that this variant is damaging. -

Mar 26, 2025

GeneDx

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 31561939, 23663589, 25891276, 23607914, 30919934, 32528171, 29431110, 34426522, 34008892) -

Jan 11, 2024

Revvity Omics, Revvity

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Autosomal recessive limb-girdle muscular dystrophy type 2L

Pathogenic:2

Oct 01, 2021

Laboratory of Medical Genetics, National & Kapodistrian University of Athens

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

PM3, PP2, PP3, PP5, BS2 -

Aug 21, 2023

3billion

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.013%). Predicted Consequence/Location: Protein truncation variants are a common disease-causing mechanism. In silico tool predictions suggest damaging effect of the variant on gene or gene product [REVEL: 0.71 (>=0.6, sensitivity 0.68 and specificity 0.92); 3Cnet: 0.65 (>=0.6, sensitivity 0.72 and precision 0.9)]. Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000285338 /PMID: 23663589). The variant has been reported to be in trans with a pathogenic variant as either compound heterozygous or homozygous in at least one similarly affected unrelated individual (PMID: 25891276). A different missense change at the same codon (p.Met833Arg) has been reported to be associated with ANO5 related disorder (PMID: 31350120). Therefore, this variant is classified as Likely pathogenic according to the recommendation of ACMG/AMP guideline. -

Autosomal recessive limb-girdle muscular dystrophy

Pathogenic:1

Jul 30, 2021

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:research

- -

ANO5-related disorder

Pathogenic:1

Aug 16, 2018

Illumina Laboratory Services, Illumina

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The ANO5 c.2498T>A (p.Met833Lys) missense variant has been reported in three studies in which it is found in three unrelated individuals affected with muscular dystrophy who had high levels of creatine kinase, including one who carried the variant in a homozygous state and two who carried the variant in a compound heterozygous state with known or suspected null variants in trans (van der Kooi et al. 2013; Liewluck et al. 2013; Savarese et al. 2015). The p.Met833Lys variant was absent from 52 control individuals (Savarese et al. 2015) and present in a heterozygous state in three unaffected first-degree relatives of probands (van der Kooi et al. 2013; Liewluck et al. 2013). The p.Met833Lys variant is reported at a frequency of 0.001085 in the Ashkenazi Jewish population of the Genome Aggregation Database. Based on the combined clinical evidence, the p.Met833Lys variant is classified as likely pathogenic for ANO5-Related Disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -

Gnathodiaphyseal dysplasia;C1969785:Autosomal recessive limb-girdle muscular dystrophy type 2L;C2750076:Miyoshi muscular dystrophy 3

Pathogenic:1

Feb 27, 2022

Fulgent Genetics, Fulgent Genetics

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Gnathodiaphyseal dysplasia;C1969785:Autosomal recessive limb-girdle muscular dystrophy type 2L

Pathogenic:1

Dec 09, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces methionine, which is neutral and non-polar, with lysine, which is basic and polar, at codon 833 of the ANO5 protein (p.Met833Lys). This variant is present in population databases (rs142073798, gnomAD 0.1%). This missense change has been observed in individual(s) with limb-girdle or distal muscular dystrophy (PMID: 23607914, 23663589, 25891276). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 285338). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt ANO5 protein function with a positive predictive value of 95%. This variant disrupts the p.Met833 amino acid residue in ANO5. Other variant(s) that disrupt this residue have been observed in individuals with ANO5-related conditions (PMID: 31350120), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.98

BayesDel_addAF

Uncertain

0.13

BayesDel_noAF

Pathogenic

0.27

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.39

Eigen

Pathogenic

0.71

Eigen_PC

Pathogenic

0.68

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.95

M_CAP

Uncertain

0.093

MetaRNN

Pathogenic

0.81

MetaSVM

Uncertain

-0.14

MutationAssessor

Uncertain

2.9

PhyloP100

8.0

PrimateAI

Uncertain

0.70

PROVEAN

Pathogenic

-4.8

REVEL

Pathogenic

0.71

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0010

Polyphen

0.95

Vest4

0.96

MVP

0.85

MPC

0.54

ClinPred

0.93

GERP RS

5.0

Varity_R

0.92

gMVP

0.95

Mutation Taster

=32/68

disease causing (ClinVar)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over