rs137854527

Variant names:

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PP1_StrongPP3PP4PM2_SupportingPM3_Strong

This summary comes from the ClinGen Evidence Repository: The NM_213599.3: c.2018A>G variant in ANO5 is a missense variant predicted to cause substitution of tyrosine by cysteine at amino acid 673 (p.Tyr673Cys). This variant has been detected in at least 6 individuals with autosomal recessive limb-girdle muscular dystrophy. Of those individuals, five had another pathogenic or likely pathogenic variant, with three confirmed in trans by parental testing (c.191dup x2, 2 pts, PMIDs: 21820307, 21186264) and two phase unknown (c.191dup, 0.5 pts, ClinVar SCV001371267.12 internal data communication; c.989dup, 0.5 pts, PMID:23606453). One individual was homozygous for the variant (0.5 pts, ClinVar SCV000767092.3 internal data communication) (PM3_Strong). At least one patient with this variant displayed a progressive limb girdle pattern of muscle weakness (PP4; PMD: 21820307). The variant has been reported to segregate with the LGMD phenotype in four affected family members from two families (PP1_Strong; PMID:21186264, 23670307). The highest population minor allele frequency in gnomAD v2.1.1 is 0.00006 (1/15424 alleles) in the European (non-Finnish) population, which is less than the ClinGen LGMD VCEP threshold (≤0.0001) for PM2_Supporting, meeting this criterion (PM2_Supporting). The computational predictor REVEL gives a score of 0.88, which exceeds the VCEP threshold of ≥0.70, evidence that correlates with impact to ANO5 function (PP3). In summary, this variant meets the criteria to be classified as Pathogenic for autosomal recessive limb girdle muscular dystrophy based on the ACMG/AMP criteria applied, as specified by the ClinGen LGMD VCEP (LGMD VCEP specifications version 1.0.0; 01/07/2025): PM3_Strong, PP1_Strong, PP4, PM2_Supporting, PP3. LINK:https://erepo.genome.network/evrepo/ui/classification/CA232789/MONDO:0015152/188

Frequency

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

Exomes 𝑓: 0.0000068 ( 0 hom. )

Consequence

ANO5
NM_213599.3 missense

Scores

14

4

1

Clinical Significance

Pathogenic reviewed by expert panel P:4O:1

Conservation

PhyloP100: 9.05

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 11 ACMG points.

PM2

For more information check the summary or visit ClinGen Evidence Repository.

PM3

For more information check the summary or visit ClinGen Evidence Repository.

PP1

For more information check the summary or visit ClinGen Evidence Repository.

PP3

For more information check the summary or visit ClinGen Evidence Repository.

PP4

For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ANO5	NM_213599.3 link	c.2018A>G	p.Tyr673Cys	missense_variant	Exon 18 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.2018A>G	p.Tyr673Cys	missense_variant	Exon 18 of 22	1	NM_213599.3	ENSP00000315371.9		Q75V66

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

1

AN:

152196

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:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000684

AC:

10

AN:

1461832

Hom.:

0

Cov.:

31

AF XY:

0.00000688

AC XY:

5

AN XY:

727216

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000719

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.00000657

AC:

1

AN:

152196

Hom.:

0

Cov.:

32

AF XY:

0.0000134

AC XY:

1

AN XY:

74364

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000712

Hom.:

0

Bravo

AF:

0.0000151

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4Other:1

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

not provided

Pathogenic:2Other:1

Apr 01, 2020

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

ANO5 @LOVD

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Feb 02, 2017

Eurofins Ntd Llc (ga)

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Autosomal recessive limb-girdle muscular dystrophy

Pathogenic:1

Jan 07, 2025

ClinGen Limb Girdle Muscular Dystrophy Variant Curation Expert Panel, ClinGen

Significance: Pathogenic

Review Status: reviewed by expert panel

Collection Method: curation

The NM_213599.3: c.2018A>G variant in ANO5 is a missense variant predicted to cause substitution of tyrosine by cysteine at amino acid 673 (p.Tyr673Cys). This variant has been detected in at least 6 individuals with autosomal recessive limb-girdle muscular dystrophy. Of those individuals, five had another pathogenic or likely pathogenic variant, with three confirmed in trans by parental testing (c.191dup x2, 2 pts, PMIDs: 21820307, 21186264) and two phase unknown (c.191dup, 0.5 pts, ClinVar SCV001371267.12 internal data communication; c.989dup, 0.5 pts, PMID: 23606453). One individual was homozygous for the variant (0.5 pts, ClinVar SCV000767092.3 internal data communication) (PM3_Strong). At least one patient with this variant displayed a progressive limb girdle pattern of muscle weakness (PP4; PMD: 21820307). The variant has been reported to segregate with the LGMD phenotype in four affected family members from two families (PP1_Strong; PMID: 21186264, 23670307). The highest population minor allele frequency in gnomAD v2.1.1 is 0.00006 (1/15424 alleles) in the European (non-Finnish) population, which is less than the ClinGen LGMD VCEP threshold (≤0.0001) for PM2_Supporting, meeting this criterion (PM2_Supporting). The computational predictor REVEL gives a score of 0.88, which exceeds the VCEP threshold of ≥0.70, evidence that correlates with impact to ANO5 function (PP3). In summary, this variant meets the criteria to be classified as Pathogenic for autosomal recessive limb girdle muscular dystrophy based on the ACMG/AMP criteria applied, as specified by the ClinGen LGMD VCEP (LGMD VCEP specifications version 1.0.0; 01/07/2025): PM3_Strong, PP1_Strong, PP4, PM2_Supporting, PP3. -

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

Pathogenic:1

Oct 08, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 673 of the ANO5 protein (p.Tyr673Cys). This variant is present in population databases (rs137854527, gnomAD 0.007%). This missense change has been observed in individual(s) with clinical features of ANO5-related conditions (PMID: 21186264, 22980763, 23606453, 23670307). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 140555). 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%. For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.92

BayesDel_addAF

Pathogenic

0.42

D

BayesDel_noAF

Pathogenic

0.37

CADD

Pathogenic

28

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.63

D

Eigen

Pathogenic

0.95

Eigen_PC

Pathogenic

0.84

FATHMM_MKL

Pathogenic

0.99

D

LIST_S2

Pathogenic

0.99

D

M_CAP

Uncertain

0.18

D

MetaRNN

Pathogenic

0.93

D

MetaSVM

Uncertain

0.72

D

MutationAssessor

Pathogenic

4.1

H

PrimateAI

Pathogenic

0.89

D

PROVEAN

Pathogenic

-8.8

D

REVEL

Pathogenic

0.88

Sift

Pathogenic

0.0

D

Sift4G

Pathogenic

0.0

D

Polyphen

1.0

D

Vest4

0.98

MutPred

0.73

Gain of catalytic residue at L674 (P = 0.0127);

MVP

0.93

MPC

0.52

ClinPred

1.0

D

GERP RS

5.7

Varity_R

0.86

gMVP

0.93

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: rs137854527; hg19: chr11-22291977;