chr11-22272895-C-G

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 0P and 3B. BP4_ModerateBS2_Supporting

The NM_213599.3(ANO5):ā€‹c.2141C>Gā€‹(p.Thr714Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000787 in 1,614,064 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: š‘“ 0.00090 ( 0 hom., cov: 32)
Exomes š‘“: 0.00078 ( 4 hom. )

Consequence

ANO5
NM_213599.3 missense

Scores

2
10
7

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:9B:1

Conservation

PhyloP100: 7.90
Variant links:
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -3 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.19104081).
BS2
High AC in GnomAd4 at 137 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 rank MANE Protein UniProt
ANO5NM_213599.3 linkc.2141C>G p.Thr714Ser missense_variant Exon 19 of 22 ENST00000324559.9 NP_998764.1 Q75V66

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
ANO5ENST00000324559.9 linkc.2141C>G p.Thr714Ser missense_variant Exon 19 of 22 1 NM_213599.3 ENSP00000315371.9 Q75V66

Frequencies

GnomAD3 genomes
AF:
0.000901
AC:
137
AN:
152122
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.000169
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00144
Gnomad ASJ
AF:
0.00202
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.000621
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00134
Gnomad OTH
AF:
0.00335
GnomAD3 exomes
AF:
0.000887
AC:
223
AN:
251442
Hom.:
1
AF XY:
0.000905
AC XY:
123
AN XY:
135890
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00101
Gnomad ASJ exome
AF:
0.00139
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00134
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00108
Gnomad OTH exome
AF:
0.00163
GnomAD4 exome
AF:
0.000776
AC:
1134
AN:
1461824
Hom.:
4
Cov.:
32
AF XY:
0.000803
AC XY:
584
AN XY:
727222
show subpopulations
Gnomad4 AFR exome
AF:
0.000149
Gnomad4 AMR exome
AF:
0.00103
Gnomad4 ASJ exome
AF:
0.00134
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00134
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.000758
Gnomad4 OTH exome
AF:
0.000927
GnomAD4 genome
AF:
0.000900
AC:
137
AN:
152240
Hom.:
0
Cov.:
32
AF XY:
0.000806
AC XY:
60
AN XY:
74438
show subpopulations
Gnomad4 AFR
AF:
0.000169
Gnomad4 AMR
AF:
0.00144
Gnomad4 ASJ
AF:
0.00202
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.000621
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00134
Gnomad4 OTH
AF:
0.00331
Alfa
AF:
0.000894
Hom.:
0
Bravo
AF:
0.000846
TwinsUK
AF:
0.000270
AC:
1
ALSPAC
AF:
0.000259
AC:
1
ESP6500AA
AF:
0.00
AC:
0
ESP6500EA
AF:
0.000814
AC:
7
ExAC
AF:
0.000750
AC:
91
Asia WGS
AF:
0.000289
AC:
1
AN:
3478
EpiCase
AF:
0.00131
EpiControl
AF:
0.00124

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:1Uncertain:9Benign:1
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

not provided Pathogenic:1Uncertain:6
Mar 07, 2023
Athena Diagnostics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

Available data are insufficient to determine the clinical significance of the variant at this time. The frequency of this variant in the general population is uninformative in assessment of its pathogenicity (http://gnomad.broadinstitute.org). In multiple individuals, this variant has been seen with a single recessive pathogenic variant in the same gene, suggesting this variant may also be pathogenic. -

Oct 23, 2023
Mayo Clinic Laboratories, Mayo Clinic
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

PM3, PS4_moderate -

Mar 08, 2023
Revvity Omics, Revvity
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Nov 07, 2023
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The ANO5 c.2141C>G; p.Thr714Ser variant (rs200631556) is reported in the literature in multiple individuals affected with limb girdle muscular dystrophy and unspecified neuromuscular disorders; however, it is only rarely found with a second pathogenic ANO5 variant (Gonzalez-Quereda 2020, Nallamilli 2018, Savarese 2015). This variant is also reported in ClinVar (Variation ID: 195004) and is found in the general population with an overall allele frequency of 0.09% (250/282,842 alleles, including 1 homozygote) in the Genome Aggregation Database. Computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.498). Due to limited information, the clinical significance of this variant is uncertain at this time. References: Gonzalez-Quereda L et al. Targeted Next-Generation Sequencing in a Large Cohort of Genetically Undiagnosed Patients with Neuromuscular Disorders in Spain. Genes (Basel). 2020 May 11;11(5):539. PMID: 32403337. Nallamilli BRR et al. Genetic landscape and novel disease mechanisms from a large LGMD cohort of 4656 patients. Ann Clin Transl Neurol. 2018 Dec 1;5(12):1574-1587. PMID: 30564623. Savarese M et al. Next generation sequencing on patients with LGMD and nonspecific myopathies: Findings associated with ANO5 mutations. Neuromuscul Disord. 2015 Jul;25(7):533-41. PMID: 25891276. -

Jan 01, 2024
CeGaT Center for Human Genetics Tuebingen
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

ANO5: PM3:Strong, PM2 -

Oct 24, 2024
GeneDx
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

Reported previously in individuals with muscular dystrophy, suspected LGMD, and/or unspecified neuromuscular disorder with myopathic changes on biopsy who harbored another ANO5 pathogenic variant; however, segregation analysis was not provided and functional characterization of the variant was not performed (PMID: 22402862, 30564623, 32403337); Reported previously in individuals with limb-girdle muscular dystrophy, suspected limb-girdle muscular dystrophy, and Miyoshi myopathy who were heterozygous for this change and did not have another identifiable ANO5 pathogenic variant; however, additional clinical information was not provided and functional characterization of the variant was not completed (PMID: 25891276, 30564623, 36352632); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 23047743, 34426522, 33023636, 30564623, 32403337, 22402862, 25891276, Schiava2022[casereport], 36913258, 35239206, 27884173, 36352632, 37526466) -

Sep 12, 2018
Eurofins Ntd Llc (ga)
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

ANO5-Related Muscle Diseases Uncertain:1
Apr 27, 2017
Illumina Laboratory Services, Illumina
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

Gnathodiaphyseal dysplasia Uncertain:1
May 28, 2019
Mendelics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Autosomal recessive limb-girdle muscular dystrophy type 2L Uncertain:1
Mar 17, 2022
MGZ Medical Genetics Center
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Gnathodiaphyseal dysplasia;C1969785:Autosomal recessive limb-girdle muscular dystrophy type 2L Benign:1
Jan 27, 2025
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.20
BayesDel_addAF
Uncertain
0.022
T
BayesDel_noAF
Pathogenic
0.22
CADD
Uncertain
23
DANN
Uncertain
0.99
DEOGEN2
Benign
0.31
T
Eigen
Uncertain
0.36
Eigen_PC
Uncertain
0.49
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Uncertain
0.90
D
M_CAP
Benign
0.022
T
MetaRNN
Benign
0.19
T
MetaSVM
Benign
-0.54
T
MutationAssessor
Uncertain
2.4
M
PrimateAI
Uncertain
0.70
T
PROVEAN
Uncertain
-3.3
D
REVEL
Uncertain
0.50
Sift
Benign
0.067
T
Sift4G
Uncertain
0.050
T
Polyphen
0.030
B
Vest4
0.85
MutPred
0.64
Gain of disorder (P = 0.0663);
MVP
0.65
MPC
0.12
ClinPred
0.088
T
GERP RS
5.6
Varity_R
0.45
gMVP
0.61

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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs200631556; hg19: chr11-22294441; COSMIC: COSV99048682; API