11-22221100-CA-CAA

Variant names:

• chr11-22221100-C-CA
• rs137854521
• NM_213599.3:c.191dupA

Variant summary

Our verdict is Pathogenic. The variant received 15 ACMG points: 15P and 0B. PP1_Strong PM3 PVS1 PP4

This summary comes from the ClinGen Evidence Repository: The NM_213599.3: c.191dup (p.Asn64LysfsTer15) variant in ANO5 is a frameshift variant observed to cause a premature stop codon in biologically relevant exon 5/22, leading to nonsense mediated decay in a gene in which loss of function is an established disease mechanism (PVS1; PMID:20096397). This variant has been detected in at least 26 individuals with autosomal recessive limb girdle muscular dystrophy, including in a homozygous state in at least eight patients (1.0 pt, PMID:20096397, 28187523, 30919934; PM3). At least one patient with this variant displayed progressive proximal muscle weakness (PP4). The variant has also been reported to segregate with autosomal recessive LGMD in 4 affected family members from 3 families (PP1_Strong; PMID:22336395, 20096397, 28187523). The filtering allele frequency of this variant is 0.001770 (the lower threshold of the 95% CI of 139/67894 genome chromosomes) in the European (non-Finnish) population in gnomAD v3.1.2, which is higher than the LGMD VCEP threshold (>0.002) for BS1; however, this variant is a frequently observed variant among affected patients and the VCEP opted not to apply this code (BS1 exception). 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 LGMD VCEP (LGMD VCEP specifications version 1.0.0; 01/09/2025): PVS1, PM3, PP4, PP1_Strong. LINK:https://erepo.genome.network/evrepo/ui/classification/CA115378/MONDO:0015152/188

• Frequency:
  • Genomes: 𝑓 0.0012 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0022 (4 hom.)
• Consequence: ANO5 NM_213599.3 frameshift
• Clinical Significance: Pathogenic reviewed by expert panel P:38 B:1 O:2
• Conservation: PhyloP100: 2.66
• Publications: 69 publications found

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 Gene-Disease associations (from GenCC):

• gnathodiaphyseal dysplasia

  Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: ClinGen, Labcorp Genetics (formerly Invitae), G2P, Orphanet
• autosomal recessive limb-girdle muscular dystrophy

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• autosomal recessive limb-girdle muscular dystrophy type 2L

  Inheritance: AR Classification: STRONG, SUPPORTIVE, LIMITED Submitted by: G2P, Labcorp Genetics (formerly Invitae), Orphanet
• Miyoshi muscular dystrophy 3

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Pathogenic. The variant received 15 ACMG points.

• PVS1: For more information check the summary or visit ClinGen Evidence Repository.
• PM3: For more information check the summary or visit ClinGen Evidence Repository.
• PP1: For more information check the summary or visit ClinGen Evidence Repository.
• PP4: For more information check the summary or visit ClinGen Evidence Repository.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_213599.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ANO5	NM_213599.3	MANE Select	c.191dupA	p.Asn64LysfsTer15	frameshift	Exon 5 of 22	NP_998764.1	Q75V66
	ANO5	NM_001142649.2		c.188dupA	p.Asn63LysfsTer15	frameshift	Exon 5 of 22	NP_001136121.1
	ANO5	NM_001410963.1		c.149dupA	p.Asn50LysfsTer15	frameshift	Exon 4 of 21	NP_001397892.1	A0A804HL91

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ANO5	ENST00000324559.9	TSL:1 MANE Select	c.191dupA	p.Asn64LysfsTer15	frameshift	Exon 5 of 22	ENSP00000315371.9	Q75V66
	ANO5	ENST00000682341.1		c.149dupA	p.Asn50LysfsTer15	frameshift	Exon 4 of 21	ENSP00000508251.1	A0A804HL91
	ANO5	ENST00000684663.1		c.146dupA	p.Asn49LysfsTer15	frameshift	Exon 4 of 21	ENSP00000508009.1	A0A804HKP2

Frequencies

GnomAD3 genomes AF: 0.00118 AC: 179 AN: 151826 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000363

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00125

Gnomad ASJ AF: 0.000577

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000946

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00205

Gnomad OTH AF: 0.00144

GnomAD2 exomes AF: 0.00110 AC: 273 AN: 249002 AF XY: 0.00110

Gnomad AFR exome AF: 0.000557

Gnomad AMR exome AF: 0.000379

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000467

Gnomad NFE exome AF: 0.00218

Gnomad OTH exome AF: 0.000826

GnomAD4 exome AF: 0.00218 AC: 3171 AN: 1457112 Hom.: 4 Cov.: 29 AF XY: 0.00217 AC XY: 1572 AN XY: 725068

African (AFR) AF: 0.000360 AC: 12 AN: 33310

American (AMR) AF: 0.000382 AC: 17 AN: 44530

Ashkenazi Jewish (ASJ) AF: 0.000653 AC: 17 AN: 26028

East Asian (EAS) AF: 0.00 AC: 0 AN: 39470

South Asian (SAS) AF: 0.00 AC: 0 AN: 86074

European-Finnish (FIN) AF: 0.000244 AC: 13 AN: 53194

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5740

European-Non Finnish (NFE) AF: 0.00273 AC: 3030 AN: 1108630

Other (OTH) AF: 0.00136 AC: 82 AN: 60136

GnomAD4 genome AF: 0.00118 AC: 179 AN: 151944 Hom.: 0 Cov.: 33 AF XY: 0.00104 AC XY: 77 AN XY: 74266

African (AFR) AF: 0.000361 AC: 15 AN: 41494

American (AMR) AF: 0.00125 AC: 19 AN: 15238

Ashkenazi Jewish (ASJ) AF: 0.000577 AC: 2 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5166

South Asian (SAS) AF: 0.00 AC: 0 AN: 4804

European-Finnish (FIN) AF: 0.0000946 AC: 1 AN: 10576

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00205 AC: 139 AN: 67886

Other (OTH) AF: 0.00142 AC: 3 AN: 2108

Alfa AF: 0.000800 Hom.: 0

Bravo AF: 0.00117

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
13	-	-	not provided (14)
11	-	-	Autosomal recessive limb-girdle muscular dystrophy type 2L (11)
3	-	-	Autosomal recessive limb-girdle muscular dystrophy (3)
2	-	-	ANO5-related disorder (3)
2	-	-	Gnathodiaphyseal dysplasia (2)
1	-	-	ANO5-related muscular dystrophy (1)
1	-	-	Autosomal recessive limb-girdle muscular dystrophy type 2L;C2750076:Miyoshi muscular dystrophy 3 (1)
1	-	-	Gnathodiaphyseal dysplasia;C1969785:Autosomal recessive limb-girdle muscular dystrophy type 2L (1)
1	-	-	Gnathodiaphyseal dysplasia;C1969785:Autosomal recessive limb-girdle muscular dystrophy type 2L;C2750076:Miyoshi muscular dystrophy 3 (1)
-	-	1	Intellectual disability (1)
1	-	-	Miyoshi muscular dystrophy 3 (1)
1	-	-	Myopathy (1)
1	-	-	Polycystic kidney disease;C0241005:Elevated circulating creatine kinase concentration;C0410264:Achilles tendon contracture;C1836296:Lower limb muscle weakness;C4024921:Lower limb amyotrophy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		2.7
Mutation Taster		=3/197	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs137854521; hg19: chr11-22242646; COSMIC: COSV61086337;