rs368970223

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PVS1PP5_Very_Strong

The NM_213599.3(ANO5):c.1213C>T(p.Gln405*) variant causes a stop gained change. The variant allele was found at a frequency of 0.0000267 in 1,611,332 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. Q405Q) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.000039 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000025 ( 0 hom. )

Consequence

ANO5
NM_213599.3 stop_gained

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:6

Conservation

PhyloP100: 5.92

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 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 16 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

PP5

Variant 11-22255403-C-T is Pathogenic according to our data. Variant chr11-22255403-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 285742.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-22255403-C-T is described in Lovd as [Pathogenic]. Variant chr11-22255403-C-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ANO5	NM_213599.3 link	c.1213C>T	p.Gln405*	stop_gained	Exon 13 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.1213C>T	p.Gln405*	stop_gained	Exon 13 of 22	1	NM_213599.3	ENSP00000315371.9		Q75V66

Frequencies

GnomAD3 genomes

AF:

0.0000395

AC:

AN:

152012

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000588

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000161

AC:

AN:

249204

AF XY:

0.0000297

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000357

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000254

AC:

AN:

1459320

Hom.:

Cov.:

AF XY:

0.0000289

AC XY:

AN XY:

726034

show subpopulations

Gnomad4 AFR exome

AF:

0.00

AC:

AN:

33452

Gnomad4 AMR exome

AF:

0.00

AC:

AN:

44698

Gnomad4 ASJ exome

AF:

0.00

AC:

AN:

26072

Gnomad4 EAS exome

AF:

0.00

AC:

AN:

39656

Gnomad4 SAS exome

AF:

0.00

AC:

AN:

86018

Gnomad4 FIN exome

AF:

0.00

AC:

AN:

53202

Gnomad4 NFE exome

AF:

0.0000333

AC:

AN:

1110222

Gnomad4 Remaining exome

AF:

0.00

AC:

AN:

60246

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

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:

0.0000395

AC:

AN:

152012

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74240

show subpopulations

Gnomad4 AFR

AF:

0.0000483

AC:

0.0000483115

AN:

0.0000483115

Gnomad4 AMR

AF:

0.00

AC:

AN:

Gnomad4 ASJ

AF:

0.00

AC:

AN:

Gnomad4 EAS

AF:

0.00

AC:

AN:

Gnomad4 SAS

AF:

0.00

AC:

AN:

Gnomad4 FIN

AF:

0.00

AC:

AN:

Gnomad4 NFE

AF:

0.0000588

AC:

0.0000588132

AN:

0.0000588132

Gnomad4 OTH

AF:

0.00

AC:

AN:

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

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:

0.0000415

Hom.:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.0000165

AC:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:3

Feb 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

ANO5: PVS1, PM2, PM3 -

Jun 21, 2017

Eurofins Ntd Llc (ga)

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

May 07, 2019

Revvity Omics, Revvity

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Muscular dystrophy

Pathogenic:1

Apr 16, 2018

SIB Swiss Institute of Bioinformatics

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:curation

The following ACMG Tag(s) were applied: PM2 => Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium. PP3 => Multiple lines of computational evidence support a deleterious effect on the gene or gene product. PVS1-Strong => PVS1 downgraded in strength to Strong. -

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

Pathogenic:1

Aug 05, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change creates a premature translational stop signal (p.Gln405*) in the ANO5 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in ANO5 are known to be pathogenic (PMID: 21186264, 23606453, 25891276, 30919934). This variant is present in population databases (rs368970223, gnomAD 0.003%). This premature translational stop signal has been observed in individuals with autosomal recessive limb girdle muscular dystrophy (PMID: 25891276). ClinVar contains an entry for this variant (Variation ID: 285742). For these reasons, this variant has been classified as Pathogenic. -

Autosomal recessive limb-girdle muscular dystrophy type 2L

Pathogenic:1

Lifecell International Pvt. Ltd

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

A Heterozygous Nonsense variant c.1213C>T in Exon 13 of the ANO5 gene that results in the amino acid substitution p.Gln405* was identified. The observed variant has a minor allele frequency of 0.00002/0.00003% in gnomAD exomes and genomes, respectively. The severity of the impact of this variant on the protein is high, based on the effect of the protein and REVEL score . Rare Exome Variant Ensemble Learner (REVEL) is an ensembl method for predicting the pathogenicity of missense variants based on a combination of scores from 13 individual tools: MutPred, FATHMM v2.3, VEST 3.0, PolyPhen-2, SIFT, PROVEAN, MutationAssessor, MutationTaster, LRT, GERP++, SiPhy, phyloP, and phastCons. The REVEL score for an individual missense variant can range from 0 to 1, with higher scores reflecting greater likelihood that the variant is disease-causing. ClinVar has also classified this variant as Pathogenic (Variant ID: 285742). The observed variant has previously been reported in the patient affected with muscular dystrophy (Hicks D et.al) Based on the above evidence this variant has been classified as Pathogenic according to the ACMG guidelines. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.58

BayesDel_noAF

Pathogenic

0.65

CADD

Pathogenic

DANN

Uncertain

1.0

Eigen

Pathogenic

0.96

Eigen_PC

Pathogenic

0.78

FATHMM_MKL

Pathogenic

0.98

Vest4

0.91

GERP RS

4.2

Mutation Taster

=1/199

disease causing (ClinVar)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.11

Details are displayed if max score is > 0.2

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over