chr11-22250950-G-A

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1_ModeratePM2PP5_Very_Strong

The NM_213599.3(ANO5):c.1120-1G>A variant causes a splice acceptor, intron change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000248 in 1,612,340 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

ANO5
NM_213599.3 splice_acceptor, intron

Scores

Splicing: ADA: 1.000

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3

Conservation

PhyloP100: 7.44

Publications

1 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: Pathogenic. The variant received 12 ACMG points.

PVS1

Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.022246536 fraction of the gene. Cryptic splice site detected, with MaxEntScore 5.4, offset of -42, new splice context is: ctcctttttattacatttAGtac. Cryptic site results in inframe change. If cryptic site found is not functional and variant results in exon loss, it results in frameshift change.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 11-22250950-G-A is Pathogenic according to our data. Variant chr11-22250950-G-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 536726.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-22250950-G-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 536726.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-22250950-G-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 536726.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-22250950-G-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 536726.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-22250950-G-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 536726.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-22250950-G-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 536726.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-22250950-G-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 536726.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-22250950-G-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 536726.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-22250950-G-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 536726.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-22250950-G-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 536726.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-22250950-G-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 536726.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-22250950-G-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 536726.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-22250950-G-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 536726.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-22250950-G-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 536726.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-22250950-G-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 536726.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-22250950-G-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 536726.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-22250950-G-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 536726.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-22250950-G-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 536726.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-22250950-G-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 536726.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-22250950-G-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 536726.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-22250950-G-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 536726.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-22250950-G-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 536726.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-22250950-G-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 536726.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-22250950-G-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 536726.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-22250950-G-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 536726.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ANO5	NM_213599.3 link	c.1120-1G>A		splice_acceptor_variant, intron_variant	Intron 11 of 21	ENST00000324559.9	NP_998764.1	Q75V66

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ANO5	ENST00000324559.9 link	c.1120-1G>A		splice_acceptor_variant, intron_variant	Intron 11 of 21	1	NM_213599.3	ENSP00000315371.9		Q75V66

Frequencies

GnomAD3 genomes

AF:

0.0000132

AC:

AN:

152082

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000385

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00000800

AC:

AN:

250156

AF XY:

0.0000148

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000109

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1460140

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

726426

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33454

American (AMR)

AF:

0.00

AC:

AN:

44696

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26122

East Asian (EAS)

AF:

0.0000253

AC:

AN:

39594

South Asian (SAS)

AF:

0.00

AC:

AN:

86212

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52902

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5762

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1111074

Other (OTH)

AF:

0.0000166

AC:

AN:

60324

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome 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

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152200

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74406

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41530

American (AMR)

AF:

0.00

AC:

AN:

15278

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.000386

AC:

AN:

5178

South Asian (SAS)

AF:

0.00

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10602

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

67996

Other (OTH)

AF:

0.00

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.450

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:

0.0000712

Hom.:

Bravo

AF:

0.0000151

ExAC

AF:

0.0000165

AC:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Autosomal recessive limb-girdle muscular dystrophy

Pathogenic:1

Oct 10, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: ANO5 c.1120-1G>A is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing and loss of ANO5 function. Several computational tools predict a significant impact on normal splicing: Four predict the variant abolishes a 3' acceptor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 8e-06 in 250156 control chromosomes. c.1120-1G>A has been reported in the literature as homozygous in individuals affected with Autosomal Recessive Limb-Girdle Muscular Dystrophy and Miyoshi myopathy (e.g. Papadopoulos_2017). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 28187523. ClinVar contains an entry for this variant (Variation ID: 536726). Based on the evidence outlined above, the variant was classified as pathogenic. -

not provided

Pathogenic:1

Oct 11, 2017

Eurofins Ntd Llc (ga)

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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

Pathogenic:1

Oct 20, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change affects an acceptor splice site in intron 11 of the ANO5 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in ANO5 are known to be pathogenic (PMID: 21186264, 23606453, 25891276, 30919934). This variant is present in population databases (rs561719071, gnomAD 0.01%). Disruption of this splice site has been observed in individual(s) with autosomal recessive distal myopathy (PMID: 28187523). ClinVar contains an entry for this variant (Variation ID: 536726). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.47

BayesDel_noAF

Pathogenic

0.41

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

Eigen

Pathogenic

1.2

Eigen_PC

Pathogenic

1.1

FATHMM_MKL

Pathogenic

0.99

PhyloP100

7.4

GERP RS

5.6

Mutation Taster

=2/98

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.93

SpliceAI score (max)

0.80

Details are displayed if max score is > 0.2

DS_AL_spliceai

0.80

Position offset: 1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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