rs563666662

Positions:

• chr11-22270368-A-G

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 14P and 1B. PM1 PM2 PP3_Moderate PP5_Very_Strong BS2_Supporting

The NM_213599.3(ANO5):​c.1955A>G​(p.Tyr652Cys) variant causes a missense change. The variant allele was found at a frequency of 0.00000342 in 1,461,840 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: ANO5 NM_213599.3 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 5.90

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]

ACMG classification

Verdict is Pathogenic. Variant got 13 ACMG points.

• PM1: In a topological_domain Extracellular (size 100) in uniprot entity ANO5_HUMAN there are 8 pathogenic changes around while only 0 benign (100%) in NM_213599.3
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.861
• PP5: Variant 11-22270368-A-G is Pathogenic according to our data. Variant chr11-22270368-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 432005.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-22270368-A-G is described in Lovd as [Pathogenic].
• BS2: High AC in GnomAdExome4 at 5 AD gene. Variant has AC lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ANO5	NM_213599.3	c.1955A>G	p.Tyr652Cys	missense_variant	18/22	ENST00000324559.9	NP_998764.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ANO5	ENST00000324559.9	c.1955A>G	p.Tyr652Cys	missense_variant	18/22	1	NM_213599.3	ENSP00000315371	P2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000342 AC: 5 AN: 1461840 Hom.: 0 Cov.: 31 AF XY: 0.00000413 AC XY: 3 AN XY: 727224

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000450

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000936 Hom.: 0

Bravo AF: 0.00000756

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Mar 16, 2016

The Y652C variant has been previously reported in two compound heterozygous siblings with limb-girdle muscular dystrophy (van der Kooi et al., 2013). It was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The Y652C variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. Additionally, this substitution occurs at a position that is conserved across species. However, in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Therefore, this variant is likely pathogenic; however, the possibility that it is benign cannot be excluded. -

Gnathodiaphyseal dysplasia;C1969785:Autosomal recessive limb-girdle muscular dystrophy type 2L Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Sep 01, 2022

For these reasons, this variant has been classified as Pathogenic. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt ANO5 protein function. ClinVar contains an entry for this variant (Variation ID: 432005). This missense change has been observed in individual(s) with limb-girdle muscular dystrophy (PMID: 23607914). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 652 of the ANO5 protein (p.Tyr652Cys). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.79
BayesDel_addAF	Pathogenic	0.29	D
BayesDel_noAF	Pathogenic	0.18
CADD	Uncertain	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.31	T
Eigen	Pathogenic	0.70
Eigen_PC	Pathogenic	0.68
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.89	D
M_CAP	Uncertain	0.20	D
MetaRNN	Pathogenic	0.86	D
MetaSVM	Uncertain	-0.28	T
MutationAssessor	Uncertain	2.3	M
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.54	T
PROVEAN	Pathogenic	-6.3	D
REVEL	Uncertain	0.51
Sift	Uncertain	0.020	D
Sift4G	Benign	0.14	T
Polyphen		1.0	D
Vest4		0.92
MutPred		0.38		Loss of phosphorylation at Y652 (P = 0.0644);
MVP		0.83
MPC		0.52
ClinPred		1.0	D
GERP RS		5.7
Varity_R		0.54
gMVP		0.77

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

Publications

LitVar

Other links and lift over

dbSNP: rs563666662; hg19: chr11-22291914; COSMIC: COSV61083827; COSMIC: COSV61083827;