rs794727350

Variant names:

• chr11-22276180-CCTT-C
• rs794727350
• NM_213599.3:c.2503_2505delTTC

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM4 PP4 PM2_Supporting PM3_Strong

This summary comes from the ClinGen Evidence Repository: The NM_213599.3: c.2503_2505del variant in ANO5 is predicted to cause a change in the length of the protein due to an in-frame deletion of one amino acid in a non-repeat region, p.(Phe835del) (PM4). This variant has been detected with a pathogenic ANO5 variant in at least four individuals with LGMD, including confirmed in trans in one patient (c.191dup, 1 pt, ClinVar SCV000767093.6 internal data communication) and in unknown phase in two patients (c.2018A>G p.(Tyr673Cys), 0.5 pts, ClinVar SCV000767093.6 internal data communication; c.191dup, 0.5 pts, ClinVar SCV000574876.19 internal data communication) (PM3_Strong). At least one patient with this variant displayed progressive limb girdle muscle weakness (PP4). The filtering allele frequency of this variant is 0.000017531 (the upper threshold of the 95% CI of 12/1109046 exome chromosomes) in the European (non-Finnish) population in gnomAD v4.1.0, which is less than the ClinGen LGMD threshold ≤0.0001 for PM2_Supporting, meeting this criterion (PM2_Supporting). In summary, this variant meets the criteria to be classified as Likely 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; 01/07/2025): PM4, PM3_Strong, PP4, PM2_Supporting. LINK:https://erepo.genome.network/evrepo/ui/classification/CA242118/MONDO:0015152/188

• Frequency:
  • Genomes: 𝑓 0.000026 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000082 (0 hom.)
• Consequence: ANO5 NM_213599.3 conservative_inframe_deletion
• Clinical Significance: Likely pathogenic reviewed by expert panel P:3 U:1
• 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 8 ACMG points.

• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PM3: For more information check the summary or visit ClinGen Evidence Repository.
• PM4: 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.2503_2505delTTC	p.Phe835del	conservative_inframe_deletion	Exon 21 of 22	ENST00000324559.9	NP_998764.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ANO5	ENST00000324559.9	c.2503_2505delTTC	p.Phe835del	conservative_inframe_deletion	Exon 21 of 22	1	NM_213599.3	ENSP00000315371.9

Frequencies

GnomAD3 genomes AF: 0.0000264 AC: 4 AN: 151608 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: 0.0000591

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000160 AC: 4 AN: 250692 Hom.: 0 AF XY: 0.00000738 AC XY: 1 AN XY: 135524

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: 0.0000353

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000823 AC: 12 AN: 1458128 Hom.: 0 AF XY: 0.00000689 AC XY: 5 AN XY: 725512

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: 0.0000108

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000264 AC: 4 AN: 151608 Hom.: 0 Cov.: 32 AF XY: 0.0000270 AC XY: 2 AN XY: 74046

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: 0.0000591

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000189

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:3 Uncertain:1

Revision: reviewed by expert panel

Submissions by phenotype

not provided Pathogenic:1 Uncertain:1

Apr 12, 2017

Eurofins Ntd Llc (ga)

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 01, 2018

CeGaT Center for Human Genetics Tuebingen

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Autosomal recessive limb-girdle muscular dystrophy Pathogenic:1

Jan 07, 2025

ClinGen Limb Girdle Muscular Dystrophy Variant Curation Expert Panel, ClinGen

Significance: Likely pathogenic

Review Status: reviewed by expert panel

Collection Method: curation

The NM_213599.3: c.2503_2505del variant in ANO5 is predicted to cause a change in the length of the protein due to an in-frame deletion of one amino acid in a non-repeat region, p.(Phe835del) (PM4). This variant has been detected with a pathogenic ANO5 variant in at least four individuals with LGMD, including confirmed in trans in one patient (c.191dup, 1 pt, ClinVar SCV000767093.6 internal data communication) and in unknown phase in two patients (c.2018A>G p.(Tyr673Cys), 0.5 pts, ClinVar SCV000767093.6 internal data communication; c.191dup, 0.5 pts, ClinVar SCV000574876.19 internal data communication) (PM3_Strong). At least one patient with this variant displayed progressive limb girdle muscle weakness (PP4). The filtering allele frequency of this variant is 0.000017531 (the upper threshold of the 95% CI of 12/1109046 exome chromosomes) in the European (non-Finnish) population in gnomAD v4.1.0, which is less than the ClinGen LGMD threshold ≤0.0001 for PM2_Supporting, meeting this criterion (PM2_Supporting). In summary, this variant meets the criteria to be classified as Likely 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; 01/07/2025): PM4, PM3_Strong, PP4, PM2_Supporting. -

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

May 20, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant, c.2503_2505del, results in the deletion of 1 amino acid(s) of the ANO5 protein (p.Phe835del), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs765340468, gnomAD 0.004%). This variant has been observed in individual(s) with clinical features of limb-girdle muscular dystrophy (Invitae). 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: 195634). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -

Computational scores

Source: dbNSFP v4.3

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: rs794727350; hg19: chr11-22297726;