NM_213599.3:c.966A>T

Variant names:

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 2P and 20B. PM1BP4_StrongBP6_Very_StrongBA1

The NM_213599.3(ANO5):c.966A>T(p.Leu322Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.54 in 1,612,376 control chromosomes in the GnomAD database, including 247,717 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. L322L) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.44 ( 17544 hom., cov: 32)

Exomes 𝑓: 0.55 ( 230173 hom. )

Consequence

ANO5
NM_213599.3 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:18O:1

Conservation

PhyloP100: 0.00100

Publications

50 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: Benign. The variant received -18 ACMG points.

PM1

In a topological_domain Extracellular (size 59) in uniprot entity ANO5_HUMAN there are 7 pathogenic changes around while only 2 benign (78%) in NM_213599.3

BP4

Computational evidence support a benign effect (MetaRNN=2.8172135E-4).

BP6

Variant 11-22250324-A-T is Benign according to our data. Variant chr11-22250324-A-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 96687.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.588 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ANO5	NM_213599.3 link	c.966A>T	p.Leu322Phe	missense_variant	Exon 10 of 22	ENST00000324559.9	NP_998764.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ANO5	ENST00000324559.9 link	c.966A>T	p.Leu322Phe	missense_variant	Exon 10 of 22	1	NM_213599.3	ENSP00000315371.9

Frequencies

GnomAD3 genomes

AF:

0.441

AC:

66910

AN:

151890

Hom.:

17535

Cov.:

show subpopulations

Gnomad AFR

AF:

0.164

Gnomad AMI

AF:

0.559

Gnomad AMR

AF:

0.415

Gnomad ASJ

AF:

0.609

Gnomad EAS

AF:

0.199

Gnomad SAS

AF:

0.499

Gnomad FIN

AF:

0.594

Gnomad MID

AF:

0.566

Gnomad NFE

AF:

0.593

Gnomad OTH

AF:

0.486

GnomAD2 exomes

AF:

0.478

AC:

119591

AN:

250046

AF XY:

0.496

show subpopulations

Gnomad AFR exome

AF:

0.157

Gnomad AMR exome

AF:

0.298

Gnomad ASJ exome

AF:

0.602

Gnomad EAS exome

AF:

0.179

Gnomad FIN exome

AF:

0.590

Gnomad NFE exome

AF:

0.586

Gnomad OTH exome

AF:

0.525

GnomAD4 exome

AF:

0.550

AC:

803860

AN:

1460368

Hom.:

230173

Cov.:

AF XY:

0.552

AC XY:

400941

AN XY:

726446

show subpopulations

African (AFR)

AF:

0.152

AC:

5084

AN:

33444

American (AMR)

AF:

0.312

AC:

13916

AN:

44652

Ashkenazi Jewish (ASJ)

AF:

0.611

AC:

15954

AN:

26106

East Asian (EAS)

AF:

0.153

AC:

6075

AN:

39602

South Asian (SAS)

AF:

0.507

AC:

43723

AN:

86186

European-Finnish (FIN)

AF:

0.581

AC:

30975

AN:

53326

Middle Eastern (MID)

AF:

0.579

AC:

3321

AN:

5732

European-Non Finnish (NFE)

AF:

0.588

AC:

653307

AN:

1111002

Other (OTH)

AF:

0.522

AC:

31505

AN:

60318

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.473

Heterozygous variant carriers

16978

33956

50933

67911

84889

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

17488

34976

52464

69952

87440

<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:

0.440

AC:

66928

AN:

152008

Hom.:

17544

Cov.:

AF XY:

0.440

AC XY:

32712

AN XY:

74276

show subpopulations

African (AFR)

AF:

0.164

AC:

6808

AN:

41496

American (AMR)

AF:

0.415

AC:

6335

AN:

15266

Ashkenazi Jewish (ASJ)

AF:

0.609

AC:

2110

AN:

3466

East Asian (EAS)

AF:

0.199

AC:

1028

AN:

5172

South Asian (SAS)

AF:

0.501

AC:

2416

AN:

4824

European-Finnish (FIN)

AF:

0.594

AC:

6260

AN:

10546

Middle Eastern (MID)

AF:

0.582

AC:

171

AN:

294

European-Non Finnish (NFE)

AF:

0.593

AC:

40262

AN:

67926

Other (OTH)

AF:

0.488

AC:

1030

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

1654

3308

4963

6617

8271

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

610

1220

1830

2440

3050

<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:

0.549

Hom.:

17185

Bravo

AF:

0.407

TwinsUK

AF:

0.576

AC:

2137

ESP6500AA

AF:

0.180

AC:

794

ESP6500EA

AF:

0.586

AC:

5041

ExAC

AF:

0.480

AC:

58309

Asia WGS

AF:

0.325

AC:

1136

AN:

3476

EpiCase

AF:

0.581

EpiControl

AF:

0.584

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:18Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:10

Aug 15, 2013

Genetic Services Laboratory, University of Chicago

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Jan 13, 2015

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

p.Leu322Phe in exon 10 of ANO5: This variant is not expected to have clinical si gnificance because it has been identified in 41.4% (3559/8600) of European Ameri can chromosomes from a broad population by the NHLBI Exome Sequencing Project (h ttp://evs.gs.washington.edu/EVS; dbSNP rs7481951).

Jul 15, 2015

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

Jul 07, 2015

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

Jan 07, 2016

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Clinical Genetics, Academic Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

Jul 12, 2017

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

not provided

Benign:1Other:1

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

ANO5 @LOVD

Significance:not provided

Review Status:no classification provided

Collection Method:literature only

Miyoshi muscular dystrophy 3

Benign:1

Jul 14, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Limb-girdle muscular dystrophy, recessive

Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

ANO5-Related Muscle Diseases

Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This 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 and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.

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

Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Gnathodiaphyseal dysplasia

Benign:1

Jul 14, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Miyoshi myopathy

Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Autosomal recessive limb-girdle muscular dystrophy type 2L

Benign:1

Jul 14, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.090

BayesDel_addAF

Benign

-0.65

BayesDel_noAF

Benign

-0.56

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.10

Eigen

Benign

-0.54

Eigen_PC

Benign

-0.45

LIST_S2

Benign

0.85

MetaRNN

Benign

0.00028

MetaSVM

Benign

-0.93

MutationAssessor

Benign

1.3

PhyloP100

0.0010

PrimateAI

Benign

0.41

PROVEAN

Benign

-2.3

Sift

Benign

0.14

Sift4G

Uncertain

0.059

Vest4

0.046

ClinPred

0.0038

GERP RS

3.0

Varity_R

0.10

gMVP

0.70

Mutation Taster

=98/2

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.050

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