chr11-22218280-G-A

Variant names:

• chr11-22218280-G-A
• rs749698519
• NM_213599.3:c.173G>A

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM5 PP5

The NM_213599.3(ANO5):​c.173G>A​(p.Arg58Gln) variant causes a missense change. The variant allele was found at a frequency of 0.0000205 in 1,461,246 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R58W) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000021 (0 hom.)
• Consequence: ANO5 NM_213599.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:4 U:3
• Conservation: PhyloP100: 6.58
• Publications: 0 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: Uncertain_significance. The variant received 3 ACMG points.

• PM5: Other missense variant is known to change same aminoacid residue: Variant chr11-22218279-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 197402.Status of the report is reviewed_by_expert_panel, 3 stars.
• PP5: Variant 11-22218280-G-A is Pathogenic according to our data. Variant chr11-22218280-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 497402.

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.173G>A	p.Arg58Gln	missense	Exon 4 of 22	NP_998764.1	Q75V66
	ANO5	NM_001142649.2		c.170G>A	p.Arg57Gln	missense	Exon 4 of 22	NP_001136121.1
	ANO5	NM_001441294.1		c.95G>A	p.Arg32Gln	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.173G>A	p.Arg58Gln	missense	Exon 4 of 22	ENSP00000315371.9	Q75V66
	ANO5	ENST00000950081.1		c.173G>A	p.Arg58Gln	missense	Exon 4 of 21	ENSP00000620140.1
	ANO5	ENST00000950082.1		c.170G>A	p.Arg57Gln	missense	Exon 4 of 20	ENSP00000620141.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000279 AC: 7 AN: 251086 AF XY: 0.0000295

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000871

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000205 AC: 30 AN: 1461246 Hom.: 0 Cov.: 32 AF XY: 0.0000248 AC XY: 18 AN XY: 726936

African (AFR) AF: 0.00 AC: 0 AN: 33436

American (AMR) AF: 0.0000673 AC: 3 AN: 44598

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26108

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

South Asian (SAS) AF: 0.000162 AC: 14 AN: 86248

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53374

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5760

European-Non Finnish (NFE) AF: 0.0000108 AC: 12 AN: 1111694

Other (OTH) AF: 0.00 AC: 0 AN: 60342

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000113

ExAC AF: 0.0000494 AC: 6

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
1	2	-	not provided (3)
2	-	-	Autosomal recessive limb-girdle muscular dystrophy type 2L (2)
-	1	-	ANO5-Related Muscle Diseases (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	Uncertain	0.51
BayesDel_addAF	Benign	-0.080	T
BayesDel_noAF	Benign	-0.12
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.072	T
Eigen	Pathogenic	0.68
Eigen_PC	Pathogenic	0.70
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.85	D
M_CAP	Benign	0.072	D
MetaRNN	Uncertain	0.67	D
MetaSVM	Benign	-0.32	T
MutationAssessor	Benign	0.97	L
PhyloP100		6.6
PrimateAI	Benign	0.46	T
PROVEAN	Benign	-0.92	N
REVEL	Uncertain	0.33
Sift	Benign	0.18	T
Sift4G	Benign	0.092	T
Polyphen		1.0	D
Vest4		0.55
MutPred		0.46		Gain of loop (P = 0.0195)
MVP		0.93
MPC		0.38
ClinPred		0.55	D
GERP RS		5.9
Varity_R		0.15
gMVP		0.42
Mutation Taster		=23/77	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs749698519; hg19: chr11-22239826; COSMIC: COSV61081629;