rs201725369

Variant names:

• chr11-22218279-C-T
• rs201725369
• NM_213599.3:c.172C>T

Your query was ambiguous. Multiple possible variants found:

• chr11-22218279-C-T
• chr11-22218279-C-A
• chr11-22218279-C-G

Variant summary

Our verdict is Pathogenic. The variant received 4 ACMG points: 4P and 0B. PM3 PP1 PP4

This summary comes from the ClinGen Evidence Repository: The NM_213599.3: c.172C>T variant in ANO5 is a missense variant predicted to cause substitution of arginine by tryptophan at amino acid 58 (p.Arg58Trp). This variant has been detected in at least seven individuals with limb girdle muscular dystrophy or persistent hyperCKemia, including in unknown phase with a pathogenic variant (c.191dup x2, 1.0 pts, PMID:22499103, 30564623, LOVD Individual #00220701) and confirmed in trans with a pathogenic variant (c.2018A>G p.(Tyr673Cys), 1.0 pt, PMID:23055322; c.148C>T p.(Arg50Ter), 1.0 pt, PMID:30564623, LOVD Individual #00078872). Three individuals were homozygous for the variant, all of whom experienced progressive muscle weakness or showed myopathic or dystrophic signs on muscle biopsy (1.0 pt, PMID:31353849, 27854218) (PM3_Very Strong). At least one patient with this variant displayed progressive limb girdle muscle weakness (PP4). The variant has also been reported to segregate with autosomal recessive LGMD in one affected family member (PP1; PMID:23055322). The Grpmax filtering allele frequency for this variant is 0.002728 in gnomAD v4.1.0 exomes (the lower bound of the 95% confidence interval of 23/5762 Middle Eastern chromosomes), which is higher than the threshold of 0.001 for BS1. The Middle Eastern genetic ancestry group also includes three homozygous individuals. However, in light of the overall evidence for this variant and the potential for late onset and subclinical presentation, the LGMD VCEP considers this variant a BS1 exception. The computational predictor REVEL gives a score of 0.572 (PP3, BP4 not met). 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; 06/24/2025): PM3_Very Strong, PP4, PP1. LINK:https://erepo.genome.network/evrepo/ui/classification/CA202865/MONDO:0015152/188

• Frequency:
  • Genomes: 𝑓 0.00015 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000070 (3 hom.)
• Consequence: ANO5 NM_213599.3 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:21
• Conservation: PhyloP100: 5.19
• Publications: 24 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 4 ACMG points.

• 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.172C>T	p.Arg58Trp	missense	Exon 4 of 22	NP_998764.1	Q75V66
	ANO5	NM_001142649.2		c.169C>T	p.Arg57Trp	missense	Exon 4 of 22	NP_001136121.1
	ANO5	NM_001441294.1		c.94C>T	p.Arg32Trp	missense	Exon 4 of 22	NP_001428223.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ANO5	ENST00000324559.9	TSL:1 MANE Select	c.172C>T	p.Arg58Trp	missense	Exon 4 of 22	ENSP00000315371.9	Q75V66
	ANO5	ENST00000950081.1		c.172C>T	p.Arg58Trp	missense	Exon 4 of 21	ENSP00000620140.1
	ANO5	ENST00000950082.1		c.169C>T	p.Arg57Trp	missense	Exon 4 of 20	ENSP00000620141.1

Frequencies

GnomAD3 genomes AF: 0.000151 AC: 23 AN: 151952 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00105

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: 0.0000588

Gnomad OTH AF: 0.000956

GnomAD2 exomes AF: 0.0000996 AC: 25 AN: 251082 AF XY: 0.0000958

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000436

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000792

Gnomad OTH exome AF: 0.000164

GnomAD4 exome AF: 0.0000698 AC: 102 AN: 1461252 Hom.: 3 Cov.: 32 AF XY: 0.0000674 AC XY: 49 AN XY: 726930

African (AFR) AF: 0.0000299 AC: 1 AN: 33440

American (AMR) AF: 0.000493 AC: 22 AN: 44598

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26106

East Asian (EAS) AF: 0.00 AC: 0 AN: 39686

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86252

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53372

Middle Eastern (MID) AF: 0.00399 AC: 23 AN: 5762

European-Non Finnish (NFE) AF: 0.0000351 AC: 39 AN: 1111694

Other (OTH) AF: 0.000249 AC: 15 AN: 60342

GnomAD4 genome AF: 0.000151 AC: 23 AN: 152070 Hom.: 0 Cov.: 32 AF XY: 0.000188 AC XY: 14 AN XY: 74326

African (AFR) AF: 0.0000241 AC: 1 AN: 41518

American (AMR) AF: 0.00105 AC: 16 AN: 15250

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5140

South Asian (SAS) AF: 0.00 AC: 0 AN: 4820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10592

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

European-Non Finnish (NFE) AF: 0.0000589 AC: 4 AN: 67962

Other (OTH) AF: 0.000946 AC: 2 AN: 2114

Alfa AF: 0.0000857 Hom.: 0

Bravo AF: 0.000261

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.0000906 AC: 11

EpiCase AF: 0.0000546

EpiControl AF: 0.000119

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
7	-	-	Autosomal recessive limb-girdle muscular dystrophy type 2L (7)
6	-	-	not provided (6)
2	-	-	Autosomal recessive limb-girdle muscular dystrophy (2)
2	-	-	Miyoshi muscular dystrophy 3 (2)
1	-	-	Abnormality of the musculature (1)
1	-	-	ANO5-related disorder (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)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.75
BayesDel_addAF	Uncertain	0.059	T
BayesDel_noAF	Pathogenic	0.17
CADD	Pathogenic	33
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.099	T
Eigen	Pathogenic	0.76
Eigen_PC	Pathogenic	0.76
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.89	D
M_CAP	Benign	0.058	D
MetaRNN	Uncertain	0.66	D
MetaSVM	Uncertain	0.025	D
MutationAssessor	Benign	0.97	L
PhyloP100		5.2
PrimateAI	Uncertain	0.59	T
PROVEAN	Uncertain	-3.1	D
REVEL	Uncertain	0.57
Sift	Uncertain	0.0060	D
Sift4G	Uncertain	0.0060	D
Polyphen		1.0	D
Vest4		0.84
MVP		0.97
MPC		0.45
ClinPred		0.92	D
GERP RS		5.9
Varity_R		0.16
gMVP		0.56
Mutation Taster		=67/33	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
Splicevardb		2.0
SpliceAI score (max)		0.050		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: rs201725369; hg19: chr11-22239825; COSMIC: COSV100202374;