rs78266558

Variant names:

• chr11-22227554-A-G
• rs78266558
• NM_213599.3:c.616A>G

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BA1

This summary comes from the ClinGen Evidence Repository: The NM_213599.3: c.616A>G variant in ANO5 is a missense variant predicted to cause substitution of threonine by alanine at amino acid 206 (p.Thr206Ala). The filtering allele frequency of this variant is 0.02707 (the lower threshold of the 95% CI of 562/250584 African/African American chromosomes in gnomAD v2.1.1), which is higher than the ClinGen LGMD VCEP threshold (>0.003) for BA1 and therefore meets this criterion (BA1). At least one patient who displayed progressive weakness and a possible congenital myopathy has been reported to have this variant (PMID:25891276); however, PP4 is not applied when BA1 is met. In summary, this variant meets the criteria to be classified as Benign 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): BA1. LINK:https://erepo.genome.network/evrepo/ui/classification/CA151833/MONDO:0015152/188

• Frequency:
  • Genomes: 𝑓 0.0087 (24 hom., cov: 32)
  • Exomes 𝑓: 0.00085 (19 hom.)
• Consequence: ANO5 NM_213599.3 missense
• Clinical Significance: Benign reviewed by expert panel B:15
• Conservation: PhyloP100: 3.96
• Publications: 4 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: Benign. The variant received -8 ACMG points.

• BA1: 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.616A>G	p.Thr206Ala	missense	Exon 7 of 22	NP_998764.1	Q75V66
	ANO5	NM_001142649.2		c.613A>G	p.Thr205Ala	missense	Exon 7 of 22	NP_001136121.1
	ANO5	NM_001410963.1		c.574A>G	p.Thr192Ala	missense	Exon 6 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.616A>G	p.Thr206Ala	missense	Exon 7 of 22	ENSP00000315371.9	Q75V66
	ANO5	ENST00000682341.1		c.574A>G	p.Thr192Ala	missense	Exon 6 of 21	ENSP00000508251.1	A0A804HL91
	ANO5	ENST00000684663.1		c.571A>G	p.Thr191Ala	missense	Exon 6 of 21	ENSP00000508009.1	A0A804HKP2

Frequencies

GnomAD3 genomes AF: 0.00868 AC: 1320 AN: 152078 Hom.: 24 Cov.: 32

Gnomad AFR AF: 0.0301

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00367

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00318

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00669

GnomAD2 exomes AF: 0.00224 AC: 562 AN: 250584 AF XY: 0.00173

Gnomad AFR exome AF: 0.0292

Gnomad AMR exome AF: 0.00183

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000106

Gnomad OTH exome AF: 0.00115

GnomAD4 exome AF: 0.000851 AC: 1243 AN: 1461266 Hom.: 19 Cov.: 32 AF XY: 0.000763 AC XY: 555 AN XY: 726932

African (AFR) AF: 0.0275 AC: 918 AN: 33424

American (AMR) AF: 0.00206 AC: 92 AN: 44596

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26108

East Asian (EAS) AF: 0.00 AC: 0 AN: 39682

South Asian (SAS) AF: 0.000151 AC: 13 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53400

Middle Eastern (MID) AF: 0.00139 AC: 8 AN: 5760

European-Non Finnish (NFE) AF: 0.0000603 AC: 67 AN: 1111688

Other (OTH) AF: 0.00240 AC: 145 AN: 60354

GnomAD4 genome AF: 0.00869 AC: 1322 AN: 152196 Hom.: 24 Cov.: 32 AF XY: 0.00847 AC XY: 630 AN XY: 74404

African (AFR) AF: 0.0300 AC: 1247 AN: 41536

American (AMR) AF: 0.00367 AC: 56 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5162

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10612

Middle Eastern (MID) AF: 0.00342 AC: 1 AN: 292

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 68000

Other (OTH) AF: 0.00662 AC: 14 AN: 2114

Alfa AF: 0.00327 Hom.: 11

Bravo AF: 0.00961

ESP6500AA AF: 0.0252 AC: 111

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00294 AC: 357

Asia WGS AF: 0.00231 AC: 8 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.000178

ClinVar

ClinVar submissions

Significance: Benign

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	2	Gnathodiaphyseal dysplasia (2)
-	-	2	not provided (2)
-	-	1	ANO5-related disorder (1)
-	-	1	ANO5-Related Muscle Diseases (1)
-	-	1	Autosomal recessive limb-girdle muscular dystrophy (1)
-	-	1	Autosomal recessive limb-girdle muscular dystrophy type 2L (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	Miyoshi muscular dystrophy 3 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.069
BayesDel_addAF	Benign	-0.58	T
BayesDel_noAF	Benign	-0.58
CADD	Benign	17
DANN	Uncertain	0.99
DEOGEN2	Benign	0.25	T
Eigen	Benign	-0.26
Eigen_PC	Benign	-0.29
FATHMM_MKL	Benign	0.54	D
LIST_S2	Benign	0.74	T
MetaRNN	Benign	0.0073	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.2	M
PhyloP100		4.0
PrimateAI	Benign	0.32	T
PROVEAN	Uncertain	-2.9	D
REVEL	Benign	0.16
Sift	Benign	0.10	T
Sift4G	Uncertain	0.045	D
Polyphen		0.28	B
Vest4		0.74
MVP		0.27
MPC		0.088
ClinPred		0.025	T
GERP RS		3.2
Varity_R		0.16
gMVP		0.58
Mutation Taster		=94/6	polymorphism

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: rs78266558; hg19: chr11-22249100;