chr11-22193514-G-C

Variant names:

• chr11-22193514-G-C
• rs1191668273
• NM_213599.3:c.22G>C

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_213599.3(ANO5):​c.22G>C​(p.Glu8Gln) 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. 14/22 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. E8K) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: ANO5 NM_213599.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.46
• 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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.2934994).

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.22G>C	p.Glu8Gln	missense	Exon 1 of 22	NP_998764.1	Q75V66
	ANO5	NM_001142649.2		c.22G>C	p.Glu8Gln	missense	Exon 1 of 22	NP_001136121.1
	ANO5	NM_001410963.1		c.22G>C	p.Glu8Gln	missense	Exon 1 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.22G>C	p.Glu8Gln	missense	Exon 1 of 22	ENSP00000315371.9	Q75V66
	ANO5	ENST00000682341.1		c.22G>C	p.Glu8Gln	missense	Exon 1 of 21	ENSP00000508251.1	A0A804HL91
	ANO5	ENST00000684663.1		c.22G>C	p.Glu8Gln	missense	Exon 1 of 21	ENSP00000508009.1	A0A804HKP2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00 AC: 0 AN: 245448 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

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 Cov.: 34

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	0.14
BayesDel_addAF	Benign	-0.061	T
BayesDel_noAF	Benign	-0.32
CADD	Benign	23
DANN	Uncertain	0.97
DEOGEN2	Benign	0.045	T
Eigen	Uncertain	0.33
Eigen_PC	Uncertain	0.24
FATHMM_MKL	Benign	0.70	D
LIST_S2	Benign	0.59	T
M_CAP	Benign	0.052	D
MetaRNN	Benign	0.29	T
MetaSVM	Benign	-0.65	T
MutationAssessor	Benign	0.0	N
PhyloP100		1.5
PrimateAI	Uncertain	0.53	T
PROVEAN	Benign	-0.25	N
REVEL	Benign	0.16
Sift	Benign	0.067	T
Sift4G	Benign	0.22	T
Polyphen		0.99	D
Vest4		0.22
MutPred		0.23		Loss of disorder (P = 0.0925)
MVP		0.81
MPC		0.095
ClinPred		0.45	T
GERP RS		3.8
PromoterAI		-0.067	Neutral
Varity_R		0.15
gMVP		0.50
Mutation Taster		=84/16	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: rs1191668273; hg19: chr11-22215060;