rs199501657

Positions:

chr11-22221158-A-G

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PP3_ModeratePP5_Very_Strong

The NM_213599.3(ANO5):c.242A>G(p.Asp81Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000596 in 1,612,050 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 (★★).

Frequency

Genomes: 𝑓 0.000099 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000055 ( 0 hom. )

Consequence

ANO5
NM_213599.3 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5

Conservation

PhyloP100: 8.70

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:

ANO5 (HGNC:):

ANO5 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 10 ACMG points.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.847

PP5

Variant 11-22221158-A-G is Pathogenic according to our data. Variant chr11-22221158-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 96679.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-22221158-A-G is described in Lovd as [Pathogenic]. Variant chr11-22221158-A-G is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ANO5	NM_213599.3 linkuse as main transcript	c.242A>G	p.Asp81Gly	missense_variant	5/22	ENST00000324559.9	NP_998764.1	Q75V66

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ANO5	ENST00000324559.9 linkuse as main transcript	c.242A>G	p.Asp81Gly	missense_variant	5/22	1	NM_213599.3	ENSP00000315371.9		Q75V66

Frequencies

GnomAD3 genomes

AF:

0.0000987

AC:

AN:

152032

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:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000377

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000162

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000156

AC:

AN:

250244

Hom.:

AF XY:

0.000163

AC XY:

AN XY:

135264

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 SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000834

Gnomad NFE exome

AF:

0.000186

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000555

AC:

AN:

1459900

Hom.:

Cov.:

AF XY:

0.0000551

AC XY:

AN XY:

726248

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.000619

Gnomad4 NFE exome

AF:

0.0000414

Gnomad4 OTH exome

AF:

0.0000332

GnomAD4 genome

AF:

0.0000986

AC:

AN:

152150

Hom.:

Cov.:

AF XY:

0.000108

AC XY:

AN XY:

74362

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000377

Gnomad4 NFE

AF:

0.000162

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000474

Hom.:

Bravo

AF:

0.0000113

ExAC

AF:

0.000222

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3476

EpiCase

AF:

0.00

EpiControl

AF:

0.000119

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:3

Likely pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 12, 2017	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Sep 22, 2015	The D81G variant has been reported previously the in compound heterozygous state in an individual with elevated CK levels and lower leg weakness (PenttilÃ¤ et al., 2012). The D81G variant has also been reported in the compound heterozygous state in 3 family members, under the age of 35, with elevated CpK levels, mild weakness, and a family history of disease (Sarkozy et al., 2012). This substitution was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The D81G variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. However, pathogenic missense variants in nearby residues have not been reported in the Human Gene Mutation Database in association with muscular dystrophy (Stenson et al., 2014). Therefore, this variant is a strong candidate for a pathogenic variant; however, the possibility that it is a benign variant cannot be excluded -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2020	- -

Autosomal recessive limb-girdle muscular dystrophy

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

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

Jul 10, 2024

Variant summary: ANO5 c.242A>G (p.Asp81Gly) results in a non-conservative amino acid change located in the Anoctamin, dimerisation domain (IPR032394) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00016 in 250244 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in ANO5 causing Limb-Girdle Muscular Dystrophy, Autosomal Recessive (0.00016 vs 0.0047), allowing no conclusion about variant significance. c.242A>G has been reported in the literature in multiple individuals affected with Limb-Girdle Muscular Dystrophy, Autosomal Recessive (e.g. Penttila_2012, Sarkozy_2012, Jarmula_2019). These data indicate that the variant is very likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 22402862, 22980763, 31395899). ClinVar contains an entry for this variant (Variation ID: 96679). Based on the evidence outlined above, the variant was classified as pathogenic. -

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

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Oct 13, 2023

This sequence change replaces aspartic acid, which is acidic and polar, with glycine, which is neutral and non-polar, at codon 81 of the ANO5 protein (p.Asp81Gly). This variant is present in population databases (rs199501657, gnomAD 0.08%). This missense change has been observed in individuals with autosomal recessive limb-girdle muscular dystrophy (PMID: 22402862, 22980763, 31395899). ClinVar contains an entry for this variant (Variation ID: 96679). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt ANO5 protein function. For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.99

BayesDel_addAF

Pathogenic

0.17

BayesDel_noAF

Pathogenic

0.27

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.50

Eigen

Pathogenic

0.84

Eigen_PC

Pathogenic

0.75

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.96

M_CAP

Uncertain

0.11

MetaRNN

Pathogenic

0.85

MetaSVM

Uncertain

0.33

MutationAssessor

Benign

1.5

PrimateAI

Uncertain

0.63

PROVEAN

Pathogenic

-6.4

REVEL

Pathogenic

0.85

Sift

Pathogenic

0.0

Sift4G

Uncertain

0.0060

Polyphen

1.0

Vest4

1.0

MutPred

0.76

Loss of stability (P = 0.0518);

MVP

0.89

MPC

0.53

ClinPred

0.86

GERP RS

5.0

Varity_R

0.98

gMVP

0.87

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

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