rs137854529

Variant names:

• chr11-22274605-C-T
• rs137854529
• NM_213599.3:c.2272C>T

Variant summary

Our verdict is Pathogenic. The variant received 8 ACMG points: 8P and 0B. PM3 PP1_Strong PP3 PP4

This summary comes from the ClinGen Evidence Repository: The NM_213599.3: c.2272C>T variant in ANO5 is a missense variant predicted to cause substitution of arginine by cysteine at amino acid 758 (p.Arg758Cys). This variant has been detected in at least 7 individuals with LGMD, five of whom had a second ANO5 variant classified as pathogenic or likely pathogenic, with one confirmed in trans by parental testing (c.191dup x5, 3.0 pts, PMID:25135358, 24803842, 21739273, 21186264). Two patients were homozygous for the variant (1.0 pt, PMID:20096397) (PM3_Very Strong). At least one patient with this variant displayed progressive limb girdle muscle weakness (PP4; PMD: 31395899). The variant has been reported to segregate with LGMD in six affected family members from three families (PP1_Strong; PMID:20096397, 27911336). The maximum minor allele frequency for this variant is 0.0003116 (40/128354 chromosomes) in the European (non-Finnish) population in gnomAD v2.1.1, which exceeds the VCEP threshold of 0.0001 for PM2 (criterion not met). The computational predictor REVEL gives a score of 0.82, which meets the VCEP threshold of ≥0.70, evidence that correlates with impact to ANO5 function (PP3). 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; 01/07/2025): PM3_Very Strong, PP4, PP1_Strong, PP3. LINK:https://erepo.genome.network/evrepo/ui/classification/CA130516/MONDO:0015152/188

• Frequency:
  • Genomes: 𝑓 0.00045 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00030 (1 hom.)
• Consequence: ANO5 NM_213599.3 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:21 O:2
• Conservation: PhyloP100: 6.04
• Publications: 37 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 8 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.
• PP3: 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.2272C>T	p.Arg758Cys	missense	Exon 20 of 22	NP_998764.1	Q75V66
	ANO5	NM_001142649.2		c.2269C>T	p.Arg757Cys	missense	Exon 20 of 22	NP_001136121.1
	ANO5	NM_001410963.1		c.2230C>T	p.Arg744Cys	missense	Exon 19 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.2272C>T	p.Arg758Cys	missense	Exon 20 of 22	ENSP00000315371.9	Q75V66
	ANO5	ENST00000682341.1		c.2230C>T	p.Arg744Cys	missense	Exon 19 of 21	ENSP00000508251.1	A0A804HL91
	ANO5	ENST00000684663.1		c.2227C>T	p.Arg743Cys	missense	Exon 19 of 21	ENSP00000508009.1	A0A804HKP2

Frequencies

GnomAD3 genomes AF: 0.000455 AC: 69 AN: 151668 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000726

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000657

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00429

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000280

Gnomad OTH AF: 0.000481

GnomAD2 exomes AF: 0.000580 AC: 145 AN: 250082 AF XY: 0.000503

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 FIN exome AF: 0.00534

Gnomad NFE exome AF: 0.000212

Gnomad OTH exome AF: 0.000329

GnomAD4 exome AF: 0.000305 AC: 444 AN: 1455736 Hom.: 1 Cov.: 33 AF XY: 0.000311 AC XY: 225 AN XY: 722916

African (AFR) AF: 0.00 AC: 0 AN: 33390

American (AMR) AF: 0.0000672 AC: 3 AN: 44644

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26024

East Asian (EAS) AF: 0.0000253 AC: 1 AN: 39546

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 85988

European-Finnish (FIN) AF: 0.00556 AC: 295 AN: 53050

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5746

European-Non Finnish (NFE) AF: 0.000108 AC: 120 AN: 1107178

Other (OTH) AF: 0.000399 AC: 24 AN: 60170

GnomAD4 genome AF: 0.000455 AC: 69 AN: 151780 Hom.: 0 Cov.: 32 AF XY: 0.000634 AC XY: 47 AN XY: 74150

African (AFR) AF: 0.0000724 AC: 3 AN: 41448

American (AMR) AF: 0.0000657 AC: 1 AN: 15232

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.00 AC: 0 AN: 4800

European-Finnish (FIN) AF: 0.00429 AC: 45 AN: 10492

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

European-Non Finnish (NFE) AF: 0.000280 AC: 19 AN: 67858

Other (OTH) AF: 0.000476 AC: 1 AN: 2102

Alfa AF: 0.000226 Hom.: 0

ExAC AF: 0.000453 AC: 55

EpiCase AF: 0.000219

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
9	-	-	not provided (10)
5	-	-	Autosomal recessive limb-girdle muscular dystrophy type 2L (5)
4	-	-	Miyoshi muscular dystrophy 3 (5)
1	-	-	ANO5 Muscle Disease (1)
1	-	-	Autosomal recessive limb-girdle muscular dystrophy (1)
1	-	-	Gnathodiaphyseal dysplasia;C1969785:Autosomal recessive limb-girdle muscular dystrophy type 2L (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.71
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Pathogenic	0.34
CADD	Pathogenic	32
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.58	D
Eigen	Pathogenic	0.81
Eigen_PC	Pathogenic	0.69
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Pathogenic	1.0	D
M_CAP	Uncertain	0.20	D
MetaRNN	Benign	0.21	T
MetaSVM	Uncertain	0.74	D
MutationAssessor	Pathogenic	4.0	H
PhyloP100		6.0
PrimateAI	Uncertain	0.68	T
PROVEAN	Pathogenic	-7.3	D
REVEL	Pathogenic	0.82
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.97
MVP		0.89
MPC		0.54
ClinPred		0.33	T
GERP RS		5.2
Varity_R		0.81
gMVP		0.94
Mutation Taster		=8/92	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs137854529; hg19: chr11-22296151; COSMIC: COSV61083245;