rs776859202

Variant names:

• chr11-22225988-GAAGAA-G
• rs776859202
• NM_213599.3:c.304_308delAAAGA

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PVS1 PP4 PM2_Supporting

This summary comes from the ClinGen Evidence Repository: The NM_213599.3: c.304_308del p.(Lys102ValfsTer2) variant in ANO5 is a frameshift variant predicted to cause a premature stop codon in biologically relevant exon 6/22, leading to nonsense mediated decay in a gene in which loss of function is an established disease mechanism (PVS1). This variant has been detected in at least one individual with progressive limb girdle muscle weakness, where it was confirmed in trans with a second frameshift variant (PMID:27862037; PP4). The filtering allele frequency of this variant is 0.000034729 (the upper threshold of the 95% CI of 28/1105382 exome chromosomes) in the European (non-Finnish) population in gnomAD v4.1.0, which is lower than the VCEP threshold (0.0001) for PM2_Supporting, meeting this criterion (PM2_Supporting). In summary, this variant meets the criteria to be classified as Pathogenic for autosomal recessive limb girdle muscular dystrophy based on the ACMG/AMP criteria applied, as specified by the ClinGen LGMD VCEP (LGMD VCEP specifications version 1.0.0; 01/09/2025): PVS1, PP4, PM2_Supporting. LINK:https://erepo.genome.network/evrepo/ui/classification/CA5922882/MONDO:0015152/188

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000024 (0 hom.)
• Consequence: ANO5 NM_213599.3 frameshift
• Clinical Significance: Pathogenic reviewed by expert panel P:5 O:1
• Conservation: PhyloP100: 8.37

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 10 ACMG points.

• PVS1: For more information check the summary or visit ClinGen Evidence Repository.
• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PP4: For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ANO5	NM_213599.3	c.304_308delAAAGA	p.Lys102ValfsTer2	frameshift_variant	Exon 6 of 22	ENST00000324559.9	NP_998764.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ANO5	ENST00000324559.9	c.304_308delAAAGA	p.Lys102ValfsTer2	frameshift_variant	Exon 6 of 22	1	NM_213599.3	ENSP00000315371.9

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152052 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: 0.00000802 AC: 2 AN: 249532 Hom.: 0 AF XY: 0.00000741 AC XY: 1 AN XY: 134952

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: 0.00

Gnomad NFE exome AF: 0.0000177

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000241 AC: 35 AN: 1453748 Hom.: 0 AF XY: 0.0000207 AC XY: 15 AN XY: 723748

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: 0.00

Gnomad4 NFE exome AF: 0.0000253

Gnomad4 OTH exome AF: 0.000117

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152052 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74256

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: 0.0000340

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5 Other:1

Revision: reviewed by expert panel

Submissions by phenotype

not provided Pathogenic:2

Oct 30, 2023

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 30919934, 34264321, 25891276, 27862037) -

Sep 19, 2016

Eurofins Ntd Llc (ga)

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Autosomal recessive limb-girdle muscular dystrophy Pathogenic:1

Jan 09, 2025

ClinGen Limb Girdle Muscular Dystrophy Variant Curation Expert Panel, ClinGen

Significance: Pathogenic

Review Status: reviewed by expert panel

Collection Method: curation

The NM_213599.3: c.304_308del p.(Lys102ValfsTer2) variant in ANO5 is a frameshift variant predicted to cause a premature stop codon in biologically relevant exon 6/22, leading to nonsense mediated decay in a gene in which loss of function is an established disease mechanism (PVS1). This variant has been detected in at least one individual with progressive limb girdle muscle weakness, where it was confirmed in trans with a second frameshift variant (PMID: 27862037; PP4). The filtering allele frequency of this variant is 0.000034729 (the upper threshold of the 95% CI of 28/1105382 exome chromosomes) in the European (non-Finnish) population in gnomAD v4.1.0, which is lower than the VCEP threshold (0.0001) for PM2_Supporting, meeting this criterion (PM2_Supporting). In summary, this variant meets the criteria to be classified as Pathogenic for autosomal recessive limb girdle muscular dystrophy based on the ACMG/AMP criteria applied, as specified by the ClinGen LGMD VCEP (LGMD VCEP specifications version 1.0.0; 01/09/2025): PVS1, PP4, PM2_Supporting. -

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

Aug 03, 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.Lys102Valfs*2) 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 (rs776859202, gnomAD 0.002%). This premature translational stop signal has been observed in individual(s) with autosomal recessive limb-girdle muscular dystrophy (PMID: 25891276, 27862037). 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: 280322). For these reasons, this variant has been classified as Pathogenic. -

Abnormality of the musculature Pathogenic:1

Jul 10, 2021

Kariminejad - Najmabadi Pathology & Genetics Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

-

GenomeConnect, ClinGen

Significance: not provided

Review Status: no classification provided

Collection Method: phenotyping only

GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs776859202; hg19: chr11-22247534;