NM_213599.3:c.553G>C

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 0P and 1B. BP4

The NM_213599.3(ANO5):c.553G>C(p.Glu185Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0004 in 1,613,420 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 Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.00018 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00042 ( 0 hom. )

Consequence

ANO5
NM_213599.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:5

Conservation

PhyloP100: 9.60

Publications

5 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: Likely_benign. The variant received -1 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.30491537).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ANO5	NM_213599.3 link	c.553G>C	p.Glu185Gln	missense_variant	Exon 7 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.553G>C	p.Glu185Gln	missense_variant	Exon 7 of 22	1	NM_213599.3	ENSP00000315371.9		Q75V66

Frequencies

GnomAD3 genomes

AF:

0.000184

AC:

AN:

152004

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000242

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000262

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000283

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000294

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000199

AC:

AN:

250706

AF XY:

0.000170

show subpopulations

Gnomad AFR exome

AF:

0.0000616

Gnomad AMR exome

AF:

0.0000871

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000924

Gnomad NFE exome

AF:

0.000371

Gnomad OTH exome

AF:

0.000327

GnomAD4 exome

AF:

0.000422

AC:

617

AN:

1461416

Hom.:

Cov.:

AF XY:

0.000400

AC XY:

291

AN XY:

727024

show subpopulations

African (AFR)

AF:

0.0000299

AC:

AN:

33436

American (AMR)

AF:

0.0000897

AC:

AN:

44614

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26122

East Asian (EAS)

AF:

0.00

AC:

AN:

39680

South Asian (SAS)

AF:

0.00

AC:

AN:

86256

European-Finnish (FIN)

AF:

0.000187

AC:

AN:

53412

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5764

European-Non Finnish (NFE)

AF:

0.000520

AC:

578

AN:

1111764

Other (OTH)

AF:

0.000398

AC:

AN:

60368

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.465

Heterozygous variant carriers

118

157

196

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.000184

AC:

AN:

152004

Hom.:

Cov.:

AF XY:

0.000135

AC XY:

AN XY:

74220

show subpopulations

African (AFR)

AF:

0.0000242

AC:

AN:

41404

American (AMR)

AF:

0.000262

AC:

AN:

15246

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5164

South Asian (SAS)

AF:

0.00

AC:

AN:

4820

European-Finnish (FIN)

AF:

0.000283

AC:

AN:

10602

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.000294

AC:

AN:

67988

Other (OTH)

AF:

0.00

AC:

AN:

2084

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.000227

Hom.:

Bravo

AF:

0.000166

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000778

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000349

AC:

ExAC

AF:

0.000247

AC:

EpiCase

AF:

0.000491

EpiControl

AF:

0.000178

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:3

Feb 12, 2018

Athena Diagnostics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 19, 2017

Eurofins Ntd Llc (ga)

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Mar 02, 2023

Revvity Omics, Revvity

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Autosomal recessive limb-girdle muscular dystrophy

Uncertain:1

Jul 30, 2021

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:research

- -

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

Uncertain:1

Nov 19, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces glutamic acid, which is acidic and polar, with glutamine, which is neutral and polar, at codon 185 of the ANO5 protein (p.Glu185Gln). This variant is present in population databases (rs140381407, gnomAD 0.03%). This variant has not been reported in the literature in individuals affected with ANO5-related conditions. ClinVar contains an entry for this variant (Variation ID: 282154). 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) has been performed for this missense variant. However, the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on ANO5 protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.16

BayesDel_addAF

Benign

-0.25

BayesDel_noAF

Benign

-0.29

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.068

Eigen

Uncertain

0.57

Eigen_PC

Uncertain

0.64

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.95

M_CAP

Benign

0.043

MetaRNN

Benign

0.30

MetaSVM

Benign

-0.45

MutationAssessor

Uncertain

2.4

PhyloP100

9.6

PrimateAI

Benign

0.36

PROVEAN

Uncertain

-2.4

REVEL

Benign

0.23

Sift

Uncertain

0.0050

Sift4G

Benign

0.12

Polyphen

0.79

Vest4

0.25

MVP

0.76

MPC

0.32

ClinPred

0.18

GERP RS

5.8

Varity_R

0.53

gMVP

0.46

Mutation Taster

=78/22

polymorphism

(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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NM_213599.3:c.553G>C

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