11-22218262-A-G

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 2P and 8B. PM1BP4_StrongBS2

The NM_213599.3(ANO5):c.155A>G(p.Asn52Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00273 in 1,613,408 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0024 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0028 ( 9 hom. )

Consequence

ANO5
NM_213599.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:6B:5

Conservation

PhyloP100: 6.14

Publications

17 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 -6 ACMG points.

PM1

In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 15 uncertain in NM_213599.3

BP4

Computational evidence support a benign effect (MetaRNN=0.037495136).

BS2

High Homozygotes in GnomAdExome4 at 9 AR,AD gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_213599.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
ANO5	NM_213599.3	MANE Select	c.155A>G	p.Asn52Ser	missense	Exon 4 of 22	NP_998764.1
ANO5	NM_001142649.2		c.152A>G	p.Asn51Ser	missense	Exon 4 of 22	NP_001136121.1
ANO5	NM_001441294.1		c.77A>G	p.Asn26Ser	missense	Exon 4 of 22	NP_001428223.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
ANO5	ENST00000324559.9	TSL:1 MANE Select	c.155A>G	p.Asn52Ser	missense	Exon 4 of 22	ENSP00000315371.9
ANO5	ENST00000682084.1		n.3329A>G		non_coding_transcript_exon	Exon 2 of 2
ANO5	ENST00000682341.1		c.139-2835A>G		intron	N/A	ENSP00000508251.1

Frequencies

GnomAD3 genomes

AF:

0.00241

AC:

367

AN:

152014

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000845

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00479

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00207

Gnomad FIN

AF:

0.000943

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00340

Gnomad OTH

AF:

0.00335

GnomAD2 exomes

AF:

0.00215

AC:

541

AN:

251140

AF XY:

0.00220

show subpopulations

Gnomad AFR exome

AF:

0.000861

Gnomad AMR exome

AF:

0.00224

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00167

Gnomad NFE exome

AF:

0.00287

Gnomad OTH exome

AF:

0.00327

GnomAD4 exome

AF:

0.00276

AC:

4033

AN:

1461276

Hom.:

Cov.:

AF XY:

0.00278

AC XY:

2020

AN XY:

726940

show subpopulations

African (AFR)

AF:

0.000568

AC:

AN:

33444

American (AMR)

AF:

0.00206

AC:

AN:

44598

Ashkenazi Jewish (ASJ)

AF:

0.0000383

AC:

AN:

26112

East Asian (EAS)

AF:

0.00

AC:

AN:

39690

South Asian (SAS)

AF:

0.00233

AC:

201

AN:

86252

European-Finnish (FIN)

AF:

0.00135

AC:

AN:

53366

Middle Eastern (MID)

AF:

0.00451

AC:

AN:

5760

European-Non Finnish (NFE)

AF:

0.00311

AC:

3455

AN:

1111714

Other (OTH)

AF:

0.00277

AC:

167

AN:

60340

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

241

482

724

965

1206

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

126

252

378

504

630

<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:

0.00241

AC:

367

AN:

152132

Hom.:

Cov.:

AF XY:

0.00219

AC XY:

163

AN XY:

74354

show subpopulations

African (AFR)

AF:

0.000843

AC:

AN:

41540

American (AMR)

AF:

0.00478

AC:

AN:

15262

Ashkenazi Jewish (ASJ)

AF:

0.000288

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5146

South Asian (SAS)

AF:

0.00207

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.000943

AC:

AN:

10606

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00340

AC:

231

AN:

67966

Other (OTH)

AF:

0.00331

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

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:

0.00250

Hom.:

Bravo

AF:

0.00250

TwinsUK

AF:

0.00405

AC:

ALSPAC

AF:

0.00337

AC:

ESP6500AA

AF:

0.000454

AC:

ESP6500EA

AF:

0.00360

AC:

ExAC

AF:

0.00190

AC:

231

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.00338

EpiControl

AF:

0.00302

ClinVar

ClinVar submissions as Germline

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (6)

Gnathodiaphyseal dysplasia (2)

not specified (2)

ANO5-Related Muscle Diseases (1)

Gnathodiaphyseal dysplasia;C1969785:Autosomal recessive limb-girdle muscular dystrophy type 2L (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.47

BayesDel_noAF

Benign

-0.45

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.060

Eigen

Uncertain

0.41

Eigen_PC

Uncertain

0.48

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Benign

0.74

M_CAP

Benign

0.077

MetaRNN

Benign

0.037

MetaSVM

Benign

-0.52

MutationAssessor

Benign

1.3

PhyloP100

6.1

PrimateAI

Benign

0.46

PROVEAN

Benign

-1.5

REVEL

Benign

0.17

Sift

Benign

0.15

Sift4G

Benign

0.35

Polyphen

0.98

Vest4

0.83

MVP

0.86

MPC

0.42

ClinPred

0.012

GERP RS

5.9

Varity_R

0.12

gMVP

0.32

Mutation Taster

=69/31

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.060

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over