rs200631556

Positions:

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):c.2141C>G(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: 𝑓 0.00090 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00078 ( 4 hom. )

Consequence

ANO5
NM_213599.3 missense

Scores

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]

ANO5 links:

ANO5 (HGNC:):

ANO5 links:

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/exons	MANE	Protein	UniProt
ANO5	NM_213599.3 linkuse as main transcript	c.2141C>G	p.Thr714Ser	missense_variant	19/22	ENST00000324559.9	NP_998764.1	Q75V66

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ANO5	ENST00000324559.9 linkuse as main transcript	c.2141C>G	p.Thr714Ser	missense_variant	19/22	1	NM_213599.3	ENSP00000315371.9		Q75V66

Frequencies

GnomAD3 genomes

AF:

0.000901

AC:

137

AN:

152122

Hom.:

Cov.:

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.:

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.:

Cov.:

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.:

Cov.:

AF XY:

0.000806

AC XY:

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.:

Bravo

AF:

0.000846

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000814

AC:

ExAC

AF:

0.000750

AC:

Asia WGS

AF:

0.000289

AC:

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

Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Oct 23, 2023	PM3, PS4_moderate -
Uncertain significance, criteria provided, single submitter	clinical testing	Athena Diagnostics	Mar 07, 2023	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. -
Likely pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2024	ANO5: PM3:Strong, PM2 -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Oct 24, 2024	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) -
Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Mar 08, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 07, 2023	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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Sep 12, 2018	- -

ANO5-Related Muscle Diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

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

Uncertain significance, criteria provided, single submitter

clinical testing

Mendelics

May 28, 2019

- -

Autosomal recessive limb-girdle muscular dystrophy type 2L

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

MGZ Medical Genetics Center

Mar 17, 2022

- -

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

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 26, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.20

BayesDel_addAF

Uncertain

0.022

BayesDel_noAF

Pathogenic

0.22

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Benign

0.31

Eigen

Uncertain

0.36

Eigen_PC

Uncertain

0.49

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.90

M_CAP

Benign

0.022

MetaRNN

Benign

0.19

MetaSVM

Benign

-0.54

MutationAssessor

Uncertain

2.4

PrimateAI

Uncertain

0.70

PROVEAN

Uncertain

-3.3

REVEL

Uncertain

0.50

Sift

Benign

0.067

Sift4G

Uncertain

0.050

Polyphen

0.030

Vest4

0.85

MutPred

0.64

Gain of disorder (P = 0.0663);

MVP

0.65

MPC

0.12

ClinPred

0.088

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over