rs115750596

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_213599.3(ANO5):c.604G>A(p.Glu202Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00187 in 1,613,342 control chromosomes in the GnomAD database, including 41 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0089 ( 20 hom., cov: 32)

Exomes 𝑓: 0.0011 ( 21 hom. )

Consequence

ANO5
NM_213599.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:14

Conservation

PhyloP100: 0.744

Publications

7 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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0053126216).

BP6

Variant 11-22227542-G-A is Benign according to our data. Variant chr11-22227542-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 263316.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00892 (1357/152064) while in subpopulation AFR AF = 0.031 (1287/41480). AF 95% confidence interval is 0.0296. There are 20 homozygotes in GnomAd4. There are 617 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 20 AR,AD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ANO5	NM_213599.3 link	c.604G>A	p.Glu202Lys	missense_variant	Exon 7 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.604G>A	p.Glu202Lys	missense_variant	Exon 7 of 22	1	NM_213599.3	ENSP00000315371.9

Frequencies

GnomAD3 genomes

AF:

0.00895

AC:

1360

AN:

151946

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0312

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00217

Gnomad ASJ

AF:

0.00260

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000191

Gnomad OTH

AF:

0.00719

GnomAD2 exomes

AF:

0.00247

AC:

618

AN:

250550

AF XY:

0.00173

show subpopulations

Gnomad AFR exome

AF:

0.0317

Gnomad AMR exome

AF:

0.00151

Gnomad ASJ exome

AF:

0.00159

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000283

Gnomad OTH exome

AF:

0.000656

GnomAD4 exome

AF:

0.00113

AC:

1655

AN:

1461278

Hom.:

Cov.:

AF XY:

0.00101

AC XY:

734

AN XY:

726936

show subpopulations

African (AFR)

AF:

0.0344

AC:

1151

AN:

33430

American (AMR)

AF:

0.00146

AC:

AN:

44592

Ashkenazi Jewish (ASJ)

AF:

0.00157

AC:

AN:

26112

East Asian (EAS)

AF:

0.00

AC:

AN:

39680

South Asian (SAS)

AF:

0.00

AC:

AN:

86242

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53396

Middle Eastern (MID)

AF:

0.00417

AC:

AN:

5760

European-Non Finnish (NFE)

AF:

0.000205

AC:

228

AN:

1111708

Other (OTH)

AF:

0.00242

AC:

146

AN:

60358

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.486

Heterozygous variant carriers

192

287

383

479

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

138

184

230

<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:

0.00892

AC:

1357

AN:

152064

Hom.:

Cov.:

AF XY:

0.00830

AC XY:

617

AN XY:

74306

show subpopulations

African (AFR)

AF:

0.0310

AC:

1287

AN:

41480

American (AMR)

AF:

0.00216

AC:

AN:

15258

Ashkenazi Jewish (ASJ)

AF:

0.00260

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5166

South Asian (SAS)

AF:

0.00

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10584

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000191

AC:

AN:

67976

Other (OTH)

AF:

0.00712

AC:

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

131

196

262

327

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<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:

0.00342

Hom.:

Bravo

AF:

0.00960

ESP6500AA

AF:

0.0340

AC:

150

ESP6500EA

AF:

0.000349

AC:

ExAC

AF:

0.00285

AC:

346

Asia WGS

AF:

0.00231

AC:

AN:

3478

EpiCase

AF:

0.000327

EpiControl

AF:

0.000356

ClinVar

Significance: Benign

Submissions summary: Benign:14

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:5

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 02, 2016

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jul 20, 2016

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

not provided

Benign:4

Feb 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

ANO5: BP4, BS1, BS2 -

Mar 16, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jun 30, 2019

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Miyoshi muscular dystrophy 3

Benign:1

Dec 05, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

ANO5-Related Muscle Diseases

Benign:1

Jan 13, 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 02, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Gnathodiaphyseal dysplasia

Benign:1

Dec 05, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Autosomal recessive limb-girdle muscular dystrophy type 2L

Benign:1

Dec 05, 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

0.071

BayesDel_addAF

Benign

-0.61

BayesDel_noAF

Benign

-0.62

CADD

Benign

(source)

DANN

Benign

0.96

DEOGEN2

Benign

0.040

Eigen

Benign

-0.43

Eigen_PC

Benign

-0.24

FATHMM_MKL

Uncertain

0.85

LIST_S2

Uncertain

0.88

MetaRNN

Benign

0.0053

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.3

PhyloP100

0.74

PrimateAI

Benign

0.34

PROVEAN

Benign

-1.6

REVEL

Benign

0.062

Sift

Benign

0.97

Sift4G

Benign

0.59

Polyphen

0.0040

Vest4

0.69

MVP

0.18

MPC

0.10

ClinPred

0.0059

GERP RS

4.8

Varity_R

0.27

gMVP

0.47

Mutation Taster

=87/13

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.13

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