rs281865480

chr11-22259733-C-CA

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 16P and 4B. PVS1 PP5_Very_Strong BS2

The NM_213599.3(ANO5):c.1627dup(p.Met543AsnfsTer11) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000199 in 1,611,024 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000020 (0 hom.)
• Consequence: ANO5 NM_213599.3 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:6
• Conservation: PhyloP100: 0.246

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 Pathogenic. Variant got 12 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PP5: Variant 11-22259733-C-CA is Pathogenic according to our data. Variant chr11-22259733-C-CA is described in ClinVar as [Pathogenic]. Clinvar id is 285942.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAdExome at 9 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ANO5	NM_213599.3	c.1627dup	p.Met543AsnfsTer11	frameshift_variant	15/22	ENST00000324559.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ANO5	ENST00000324559.9	c.1627dup	p.Met543AsnfsTer11	frameshift_variant	15/22	1	NM_213599.3	P2

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152084 Hom.: 0 Cov.: 32

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: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000360 AC: 9 AN: 250076 Hom.: 0 AF XY: 0.0000370 AC XY: 5 AN XY: 135190

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000116

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000443

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000199 AC: 29 AN: 1458940 Hom.: 0 Cov.: 31 AF XY: 0.0000193 AC XY: 14 AN XY: 725948

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000895

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000207

Gnomad4 OTH exome AF: 0.0000332

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152084 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74302

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: 0.00

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000151

EpiCase AF: 0.0000545

EpiControl AF: 0.000178

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Miyoshi muscular dystrophy 3 Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Laboratory of Medical Genetics, National & Kapodistrian University of Athens	Oct 01, 2021	PVS1, PM2, PP3 -
Pathogenic, criteria provided, single submitter	curation	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	Jan 25, 2023	The homozygous p.Met543AsnfsTer11 variant in ANO5 was identified by our study in one individual with limb-girdle muscular dystrophy. The p.Met543AsnfsTer11 variant in ANO5 has been previously reported in 8 unrelated individuals with ANO5-related muscle disease (PMID: 34008892, PMID: 30919934, PMID: 25891276, PMID: 23606453, PMID: 22742934, PMID: 22402862, PMID: 22194990) and segregated with disease in 4 affected relatives from 2 families, but has been identified in 0.01% (4/35334) of Latino/Admixed American chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs1412514693). Although this variant has been seen in the general population in a heterozygous state, its frequency is low enough to be consistent with a recessive carrier frequency. Of these 8 affected individuals, 3 were homozygotes (PMID: 30919934, PMID: 25891276, PMID: 22742934) and 4 were compound heterozygotes who carried pathogenic or likely pathogenic variants in trans (PMID: 22194990, PMID: 23606453, ClinVar Variation ID: 2164; PMID: 34008892, ClinVar Variation ID: 2166), which increases the likelihood that the p.Met543AsnfsTer11 variant is pathogenic. This variant has also been reported in ClinVar (Variation ID: 285942) and has been interpreted as pathogenic by multiple submitters. This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 543 and leads to a premature termination codon 11 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Loss of function of the ANO5 gene is an established disease mechanism in autosomal recessive ANO5-related muscle disease. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive ANO5-related muscle disease. ACMG/AMP Criteria applied: PVS1, PM2_Supporting, PM3_VeryStrong, PP1 (Richards 2015). -

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

Pathogenic, criteria provided, single submitter	research	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	-	The homozgous c.1627dupA variant was identified by our study in one individual with Limb-Girdle Muscular Dystrophy. The c.1627dupA variant is believed to be pathogenic based on numberous reports by other laboratories in the literature and databases. -
Pathogenic, criteria provided, single submitter	clinical testing	MGZ Medical Genetics Center	Jul 15, 2022	- -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Jan 25, 2016

The c.1627dupA ANO5 pathogenic variant has been reported in individuals with LGMD2L1 and is of a type expected to cause disease. 1. www.lovd.nl/ANO5 AKT 9-7-16 -

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

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Oct 23, 2023

This sequence change creates a premature translational stop signal (p.Met543Asnfs*11) 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 (rs768746440, gnomAD 0.01%). This premature translational stop signal has been observed in individuals with ANO5-related myopathies and/or limb girdle muscular dystrophy 2L (PMID: 22194990, 22402862, 22742934, 23606453, 25891276). ClinVar contains an entry for this variant (Variation ID: 285942). For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.25		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.25		Position offset: 8

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

Publications

LitVar

Other links and lift over

dbSNP: rs281865480; hg19: chr11-22281279;