rs142073798

chr11-22276177-T-Achr11-22276177-T-G

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 11P and 4B. PM5 PP3 PP5_Very_Strong BS2

The NM_213599.3(ANO5):c.2498T>A(p.Met833Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000101 in 1,610,652 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M833R) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.00013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000098 (0 hom.)
• Consequence: ANO5 NM_213599.3 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:9
• Conservation: PhyloP100: 7.95

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 7 ACMG points.

• PM5: Other missense variant is known to change same aminoacid residue: Variant chr11-22276177-T-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 2430738.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Likely_pathogenic=1}.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.809
• PP5: Variant 11-22276177-T-A is Pathogenic according to our data. Variant chr11-22276177-T-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 285338.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-22276177-T-A is described in Lovd as [Likely_pathogenic]. Variant chr11-22276177-T-A is described in Lovd as [Pathogenic]. Variant chr11-22276177-T-A is described in Lovd as [Pathogenic]. Variant chr11-22276177-T-A is described in Lovd as [Likely_pathogenic].
• BS2: High AC in GnomAd at 20 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ANO5	NM_213599.3	c.2498T>A	p.Met833Lys	missense_variant	21/22	ENST00000324559.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ANO5	ENST00000324559.9	c.2498T>A	p.Met833Lys	missense_variant	21/22	1	NM_213599.3	P2

Frequencies

GnomAD3 genomes AF: 0.000132 AC: 20 AN: 151824 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000657

Gnomad ASJ AF: 0.00173

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000162

Gnomad OTH AF: 0.000479

GnomAD3 exomes AF: 0.000120 AC: 30 AN: 250750 Hom.: 0 AF XY: 0.000125 AC XY: 17 AN XY: 135564

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00109

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000159

Gnomad OTH exome AF: 0.000164

GnomAD4 exome AF: 0.0000980 AC: 143 AN: 1458828 Hom.: 0 Cov.: 31 AF XY: 0.0000951 AC XY: 69 AN XY: 725810

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00157

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000829

Gnomad4 OTH exome AF: 0.000149

GnomAD4 genome AF: 0.000132 AC: 20 AN: 151824 Hom.: 0 Cov.: 32 AF XY: 0.000135 AC XY: 10 AN XY: 74174

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.0000657

Gnomad4 ASJ AF: 0.00173

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000162

Gnomad4 OTH AF: 0.000479

Alfa AF: 0.000284 Hom.: 0

Bravo AF: 0.000113

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.000132 AC: 16

EpiCase AF: 0.0000546

EpiControl AF: 0.000119

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:5

Likely pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jan 11, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Mar 18, 2022	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 23663589, 25891276, 23607914, 30919934, 32528171, 29431110, 34426522, 34008892) -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Feb 27, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	Oct 23, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	May 05, 2023	The frequency of this variant in the general population is consistent with pathogenicity (http://gnomad.broadinstitute.org). This variant has been identified in multiple unrelated individuals with autosomal recessive limb-girdle muscular dystrophy. In multiple individuals, this variant has been seen with a single recessive pathogenic variant in the same gene, suggesting this variant may also be pathogenic. Computational tools predict that this variant is damaging. -

ANO5-related disorder Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Aug 16, 2018

The ANO5 c.2498T>A (p.Met833Lys) missense variant has been reported in three studies in which it is found in three unrelated individuals affected with muscular dystrophy who had high levels of creatine kinase, including one who carried the variant in a homozygous state and two who carried the variant in a compound heterozygous state with known or suspected null variants in trans (van der Kooi et al. 2013; Liewluck et al. 2013; Savarese et al. 2015). The p.Met833Lys variant was absent from 52 control individuals (Savarese et al. 2015) and present in a heterozygous state in three unaffected first-degree relatives of probands (van der Kooi et al. 2013; Liewluck et al. 2013). The p.Met833Lys variant is reported at a frequency of 0.001085 in the Ashkenazi Jewish population of the Genome Aggregation Database. Based on the combined clinical evidence, the p.Met833Lys variant is classified as likely pathogenic for ANO5-Related Disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -

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

Likely pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Feb 27, 2022

- -

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

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Jan 10, 2024

This sequence change replaces methionine, which is neutral and non-polar, with lysine, which is basic and polar, at codon 833 of the ANO5 protein (p.Met833Lys). This variant is present in population databases (rs142073798, gnomAD 0.1%). This missense change has been observed in individual(s) with limb girdle or distal muscular dystrophy (PMID: 23607914, 23663589, 25891276). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 285338). 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 with a positive predictive value of 80%. This variant disrupts the p.Met833 amino acid residue in ANO5. Other variant(s) that disrupt this residue have been observed in individuals with ANO5-related conditions (PMID: 31350120), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic. -

Autosomal recessive limb-girdle muscular dystrophy type 2L Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Laboratory of Medical Genetics, National & Kapodistrian University of Athens

Oct 01, 2021

PM3, PP2, PP3, PP5, BS2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Uncertain	0.13	D
BayesDel_noAF	Pathogenic	0.27
Cadd	Pathogenic	28
Dann	Uncertain	0.99
DEOGEN2	Benign	0.39	T
Eigen	Pathogenic	0.71
Eigen_PC	Pathogenic	0.68
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.95	D
M_CAP	Uncertain	0.093	D
MetaRNN	Pathogenic	0.81	D
MetaSVM	Uncertain	-0.14	T
MutationAssessor	Uncertain	2.9	M
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.70	T
PROVEAN	Pathogenic	-4.8	D
REVEL	Pathogenic	0.71
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0010	D
Polyphen		0.95	P
Vest4		0.96
MVP		0.85
MPC		0.54
ClinPred		0.93	D
GERP RS		5.0
Varity_R		0.92
gMVP		0.95

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

Other links and lift over

dbSNP: rs142073798; hg19: chr11-22297723;