chr11-22259649-C-T

Position:

• chr11-22259649-C-T

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM2 PP5_Very_Strong

The NM_213599.3(ANO5):​c.1538C>T​(p.Thr513Ile) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: ANO5 NM_213599.3 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3 U:1
• Conservation: PhyloP100: 6.16

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 10 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 11-22259649-C-T is Pathogenic according to our data. Variant chr11-22259649-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 288853.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-22259649-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ANO5	NM_213599.3	c.1538C>T	p.Thr513Ile	missense_variant	15/22	ENST00000324559.9	NP_998764.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ANO5	ENST00000324559.9	c.1538C>T	p.Thr513Ile	missense_variant	15/22	1	NM_213599.3	ENSP00000315371	P2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3 Uncertain:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2 Uncertain:1

Likely pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jun 07, 2019	- -
Uncertain significance, flagged submission	clinical testing	Eurofins Ntd Llc (ga)	Jun 19, 2016	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Nov 10, 2020	Published functional studies demonstrate that T513I leads to phospholipid scrambling, suggesting a gain-of-function effect (Di Zanni et al., 2017); Not observed in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 32112655, 28176803, 27216912, 29175271, 29124309, 23047743) -

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

Aug 10, 2023

For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects ANO5 function (PMID: 29124309). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on ANO5 protein function. ClinVar contains an entry for this variant (Variation ID: 288853). This missense change has been observed in individual(s) with autosomal dominant gnathodiaphyseal dysplasia (PMID: 23047743). 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 threonine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 513 of the ANO5 protein (p.Thr513Ile). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.22
BayesDel_addAF	Uncertain	0.079	D
BayesDel_noAF	Benign	-0.12
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.060	T
Eigen	Benign	0.058
Eigen_PC	Benign	0.18
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.96	D
M_CAP	Uncertain	0.24	D
MetaRNN	Uncertain	0.45	T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	0.74	N
MutationTaster	Benign	0.94	N
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-1.7	N
REVEL	Benign	0.25
Sift	Benign	0.34	T
Sift4G	Benign	0.23	T
Polyphen		0.51	P
Vest4		0.45
MutPred		0.54		Loss of catalytic residue at T513 (P = 0.0681);
MVP		0.73
MPC		0.33
ClinPred		0.96	D
GERP RS		5.5
Varity_R		0.13
gMVP		0.52

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: rs281865467; hg19: chr11-22281195;