11-22279721-A-G

Variant names:

• chr11-22279721-A-G
• rs148293985
• NM_213599.3:c.2698A>G

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_213599.3(ANO5):​c.2698A>G​(p.Met900Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M900L) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: ANO5 NM_213599.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.480
• 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.054890573).

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.2698A>G	p.Met900Val	missense	Exon 22 of 22	NP_998764.1	Q75V66
	ANO5	NM_001142649.2		c.2695A>G	p.Met899Val	missense	Exon 22 of 22	NP_001136121.1
	ANO5	NM_001410963.1		c.2656A>G	p.Met886Val	missense	Exon 21 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.2698A>G	p.Met900Val	missense	Exon 22 of 22	ENSP00000315371.9	Q75V66
	ANO5	ENST00000682341.1		c.2656A>G	p.Met886Val	missense	Exon 21 of 21	ENSP00000508251.1	A0A804HL91
	ANO5	ENST00000684663.1		c.2653A>G	p.Met885Val	missense	Exon 21 of 21	ENSP00000508009.1	A0A804HKP2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	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	Benign	0.077
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.55
CADD	Benign	0.21
DANN	Benign	0.84
DEOGEN2	Benign	0.046	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.046	N
LIST_S2	Benign	0.71	T
M_CAP	Benign	0.025	D
MetaRNN	Benign	0.055	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.81	L
PhyloP100		-0.48
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-0.59	N
REVEL	Benign	0.083
Sift	Benign	0.79	T
Sift4G	Benign	0.93	T
Polyphen		0.0010	B
Vest4		0.075
MutPred		0.35		Loss of catalytic residue at M900 (P = 0.0055)
MVP		0.36
MPC		0.087
ClinPred		0.022	T
GERP RS		-3.9
Varity_R		0.055
gMVP		0.36
Mutation Taster		=98/2	polymorphism

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: rs148293985; hg19: chr11-22301267; COSMIC: COSV61087802; COSMIC: COSV61087802;