rs61746201

Variant names:

• chr11-22274592-A-G
• rs61746201
• NM_213599.3:c.2259A>G

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6 BP7 BA1

The NM_213599.3(ANO5):​c.2259A>G​(p.Ser753Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00314 in 1,604,686 control chromosomes in the GnomAD database, including 160 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.016 (68 hom., cov: 32)
  • Exomes 𝑓: 0.0017 (92 hom.)
• Consequence: ANO5 NM_213599.3 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:6
• Conservation: PhyloP100: -2.76
• Publications: 5 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: G2P, ClinGen, Labcorp Genetics (formerly Invitae), 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, Orphanet, Labcorp Genetics (formerly Invitae)
• Miyoshi muscular dystrophy 3

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

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BP6: Variant 11-22274592-A-G is Benign according to our data. Variant chr11-22274592-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 128389.
• BP7: Synonymous conserved (PhyloP=-2.76 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0552 is higher than 0.05.

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.2259A>G	p.Ser753Ser	synonymous	Exon 20 of 22	NP_998764.1	Q75V66
	ANO5	NM_001142649.2		c.2256A>G	p.Ser752Ser	synonymous	Exon 20 of 22	NP_001136121.1
	ANO5	NM_001410963.1		c.2217A>G	p.Ser739Ser	synonymous	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.2259A>G	p.Ser753Ser	synonymous	Exon 20 of 22	ENSP00000315371.9	Q75V66
	ANO5	ENST00000682341.1		c.2217A>G	p.Ser739Ser	synonymous	Exon 19 of 21	ENSP00000508251.1	A0A804HL91
	ANO5	ENST00000684663.1		c.2214A>G	p.Ser738Ser	synonymous	Exon 19 of 21	ENSP00000508009.1	A0A804HKP2

Frequencies

GnomAD3 genomes AF: 0.0164 AC: 2482 AN: 151586 Hom.: 67 Cov.: 32

Gnomad AFR AF: 0.0567

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00717

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000208

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000192

Gnomad OTH AF: 0.00911

GnomAD2 exomes AF: 0.00423 AC: 1054 AN: 249152 AF XY: 0.00313

Gnomad AFR exome AF: 0.0584

Gnomad AMR exome AF: 0.00253

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000142

Gnomad OTH exome AF: 0.000165

GnomAD4 exome AF: 0.00175 AC: 2536 AN: 1452982 Hom.: 92 Cov.: 33 AF XY: 0.00151 AC XY: 1090 AN XY: 721022

African (AFR) AF: 0.0635 AC: 2118 AN: 33336

American (AMR) AF: 0.00259 AC: 115 AN: 44438

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25952

East Asian (EAS) AF: 0.00 AC: 0 AN: 39466

South Asian (SAS) AF: 0.000128 AC: 11 AN: 85770

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52868

Middle Eastern (MID) AF: 0.00157 AC: 9 AN: 5730

European-Non Finnish (NFE) AF: 0.0000461 AC: 51 AN: 1105384

Other (OTH) AF: 0.00386 AC: 232 AN: 60038

GnomAD4 genome AF: 0.0165 AC: 2502 AN: 151704 Hom.: 68 Cov.: 32 AF XY: 0.0156 AC XY: 1158 AN XY: 74130

African (AFR) AF: 0.0571 AC: 2361 AN: 41364

American (AMR) AF: 0.00709 AC: 108 AN: 15226

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5168

South Asian (SAS) AF: 0.00 AC: 0 AN: 4798

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10518

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.000192 AC: 13 AN: 67850

Other (OTH) AF: 0.00901 AC: 19 AN: 2108

Alfa AF: 0.00693 Hom.: 32

Bravo AF: 0.0187

Asia WGS AF: 0.00433 AC: 15 AN: 3478

EpiCase AF: 0.0000547

EpiControl AF: 0.000119

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	3	not specified (3)
-	-	1	ANO5-Related Muscle Diseases (1)
-	-	1	Gnathodiaphyseal dysplasia;C1969785:Autosomal recessive limb-girdle muscular dystrophy type 2L (1)
-	1	-	Limb-girdle muscular dystrophy, recessive (1)
-	1	-	Miyoshi myopathy (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.27
DANN	Benign	0.42
PhyloP100		-2.8
Mutation Taster		=98/2	polymorphism (auto)

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: rs61746201; hg19: chr11-22296138;