rs137854523

Variant names:

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 8P and 2B. PP5_Very_StrongBP4BS2_Supporting

The NM_213599.3(ANO5):c.692G>T(p.Gly231Val) variant causes a missense change. The variant allele was found at a frequency of 0.00132 in 1,613,328 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.00097 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0014 ( 4 hom. )

Consequence

ANO5
NM_213599.3 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:27O:2

Conservation

PhyloP100: 5.82

Publications

29 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):

gnathodiaphyseal dysplasia
Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: ClinGen, Labcorp Genetics (formerly Invitae), G2P, Orphanet
autosomal recessive limb-girdle muscular dystrophy
Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
autosomal recessive limb-girdle muscular dystrophy type 2L
Inheritance: AR Classification: STRONG, SUPPORTIVE, LIMITED Submitted by: G2P, Labcorp Genetics (formerly Invitae), Orphanet
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_pathogenic. The variant received 6 ACMG points.

PP5

Variant 11-22236206-G-T is Pathogenic according to our data. Variant chr11-22236206-G-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 2165.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP4

Computational evidence support a benign effect (MetaRNN=0.07639387). . Strength limited to SUPPORTING due to the PP5.

BS2

High Homozygotes in GnomAdExome4 at 4 AR,AD geneVariant has number of homozygotes lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

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	UniProt
ANO5	NM_213599.3	MANE Select	c.692G>T	p.Gly231Val	missense	Exon 8 of 22	NP_998764.1	Q75V66
ANO5	NM_001142649.2		c.689G>T	p.Gly230Val	missense	Exon 8 of 22	NP_001136121.1
ANO5	NM_001410963.1		c.650G>T	p.Gly217Val	missense	Exon 7 of 21	NP_001397892.1	A0A804HL91

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ANO5	ENST00000324559.9	TSL:1 MANE Select	c.692G>T	p.Gly231Val	missense	Exon 8 of 22	ENSP00000315371.9	Q75V66
ANO5	ENST00000682341.1		c.650G>T	p.Gly217Val	missense	Exon 7 of 21	ENSP00000508251.1	A0A804HL91
ANO5	ENST00000684663.1		c.647G>T	p.Gly216Val	missense	Exon 7 of 21	ENSP00000508009.1	A0A804HKP2

Frequencies

GnomAD3 genomes

AF:

0.000973

AC:

148

AN:

152106

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000169

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00249

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:

0.00146

Gnomad OTH

AF:

0.000479

GnomAD2 exomes

AF:

0.00103

AC:

258

AN:

250958

AF XY:

0.000907

show subpopulations

Gnomad AFR exome

AF:

0.000185

Gnomad AMR exome

AF:

0.00275

Gnomad ASJ exome

AF:

0.000298

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000463

Gnomad NFE exome

AF:

0.00123

Gnomad OTH exome

AF:

0.00262

GnomAD4 exome

AF:

0.00135

AC:

1979

AN:

1461104

Hom.:

Cov.:

AF XY:

0.00125

AC XY:

911

AN XY:

726886

show subpopulations

African (AFR)

AF:

0.000209

AC:

AN:

33442

American (AMR)

AF:

0.00269

AC:

120

AN:

44684

Ashkenazi Jewish (ASJ)

AF:

0.000536

AC:

AN:

26114

East Asian (EAS)

AF:

0.00

AC:

AN:

39572

South Asian (SAS)

AF:

0.0000116

AC:

AN:

86240

European-Finnish (FIN)

AF:

0.0000937

AC:

AN:

53386

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5760

European-Non Finnish (NFE)

AF:

0.00158

AC:

1756

AN:

1111554

Other (OTH)

AF:

0.00126

AC:

AN:

60352

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.466

Heterozygous variant carriers

194

291

388

485

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

132

198

264

330

<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:

0.000972

AC:

148

AN:

152224

Hom.:

Cov.:

AF XY:

0.000820

AC XY:

AN XY:

74434

show subpopulations

African (AFR)

AF:

0.000168

AC:

AN:

41550

American (AMR)

AF:

0.00249

AC:

AN:

15280

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3466

East Asian (EAS)

AF:

0.00

AC:

AN:

5178

South Asian (SAS)

AF:

0.00

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.000283

AC:

AN:

10614

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00146

AC:

AN:

67992

Other (OTH)

AF:

0.000474

AC:

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

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:

0.00110

Hom.:

Bravo

AF:

0.00116

TwinsUK

AF:

0.00162

AC:

ALSPAC

AF:

0.00259

AC:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.00116

AC:

ExAC

AF:

0.00105

AC:

128

EpiCase

AF:

0.00153

EpiControl

AF:

0.000771

ClinVar

ClinVar submissions

Significance:Pathogenic/Likely pathogenic

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (12)

Autosomal recessive limb-girdle muscular dystrophy type 2L (9)

ANO5-related disorder (2)

Acute rhabdomyolysis (1)

Autosomal recessive limb-girdle muscular dystrophy (1)

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

Gnathodiaphyseal dysplasia;C1969785:Autosomal recessive limb-girdle muscular dystrophy type 2L;C2750076:Miyoshi muscular dystrophy 3 (1)

Hereditary fructosuria (1)

Miyoshi muscular dystrophy 3 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.51

BayesDel_addAF

Benign

-0.13

BayesDel_noAF

Uncertain

0.030

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.36

Eigen

Pathogenic

0.77

Eigen_PC

Pathogenic

0.77

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Uncertain

0.89

M_CAP

Benign

0.078

MetaRNN

Benign

0.076

MetaSVM

Benign

-0.29

MutationAssessor

Pathogenic

3.0

PhyloP100

5.8

PrimateAI

Benign

0.42

PROVEAN

Pathogenic

-5.3

REVEL

Uncertain

0.49

Sift

Benign

0.070

Sift4G

Uncertain

0.051

Polyphen

1.0

Vest4

0.81

MVP

0.91

MPC

0.52

ClinPred

0.092

GERP RS

5.8

Varity_R

0.75

gMVP

0.67

Mutation Taster

=67/33

disease causing (ClinVar)

(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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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

Computational scores

Splicing

Publications

Other links and lift over