11-22221183-T-C

Variant names:

• chr11-22221183-T-C
• rs4312063
• NM_213599.3:c.267T>C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_213599.3(ANO5):​c.267T>C​(p.Asp89Asp) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.8 in 1,610,396 control chromosomes in the GnomAD database, including 518,819 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.83 (52348 hom., cov: 32)
  • Exomes 𝑓: 0.80 (466471 hom.)
• Consequence: ANO5 NM_213599.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:19 O:2
• Conservation: PhyloP100: -0.700

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 Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 11-22221183-T-C is Benign according to our data. Variant chr11-22221183-T-C is described in ClinVar as [Benign]. Clinvar id is 96681.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-22221183-T-C is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-0.7 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.922 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ANO5	NM_213599.3	c.267T>C	p.Asp89Asp	synonymous_variant	Exon 5 of 22	ENST00000324559.9	NP_998764.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ANO5	ENST00000324559.9	c.267T>C	p.Asp89Asp	synonymous_variant	Exon 5 of 22	1	NM_213599.3	ENSP00000315371.9

Frequencies

GnomAD3 genomes AF: 0.826 AC: 125391 AN: 151818 Hom.: 52294 Cov.: 32

Gnomad AFR AF: 0.930

Gnomad AMI AF: 0.877

Gnomad AMR AF: 0.719

Gnomad ASJ AF: 0.753

Gnomad EAS AF: 0.560

Gnomad SAS AF: 0.806

Gnomad FIN AF: 0.820

Gnomad MID AF: 0.803

Gnomad NFE AF: 0.813

Gnomad OTH AF: 0.810

GnomAD3 exomes AF: 0.766 AC: 191380 AN: 249920 Hom.: 74791 AF XY: 0.772 AC XY: 104239 AN XY: 135078

Gnomad AFR exome AF: 0.936

Gnomad AMR exome AF: 0.601

Gnomad ASJ exome AF: 0.744

Gnomad EAS exome AF: 0.554

Gnomad SAS exome AF: 0.801

Gnomad FIN exome AF: 0.820

Gnomad NFE exome AF: 0.807

Gnomad OTH exome AF: 0.780

GnomAD4 exome AF: 0.797 AC: 1162290 AN: 1458460 Hom.: 466471 Cov.: 42 AF XY: 0.797 AC XY: 578577 AN XY: 725672

Gnomad4 AFR exome AF: 0.936

Gnomad4 AMR exome AF: 0.615

Gnomad4 ASJ exome AF: 0.752

Gnomad4 EAS exome AF: 0.527

Gnomad4 SAS exome AF: 0.803

Gnomad4 FIN exome AF: 0.812

Gnomad4 NFE exome AF: 0.810

Gnomad4 OTH exome AF: 0.794

GnomAD4 genome AF: 0.826 AC: 125507 AN: 151936 Hom.: 52348 Cov.: 32 AF XY: 0.823 AC XY: 61097 AN XY: 74240

Gnomad4 AFR AF: 0.930

Gnomad4 AMR AF: 0.719

Gnomad4 ASJ AF: 0.753

Gnomad4 EAS AF: 0.559

Gnomad4 SAS AF: 0.806

Gnomad4 FIN AF: 0.820

Gnomad4 NFE AF: 0.813

Gnomad4 OTH AF: 0.812

Alfa AF: 0.803 Hom.: 53933

Bravo AF: 0.815

Asia WGS AF: 0.724 AC: 2518 AN: 3474

EpiCase AF: 0.800

EpiControl AF: 0.800

ClinVar

Significance: Benign

Submissions summary: Benign:19 Other:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:10

Jul 10, 2013

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 13, 2015

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

p.Asp89Asp in exon 5 of ANO5: This variant is not expected to have clinical sign ificance because it does not alter an amino acid residue and is not located with in the splice consensus sequence. It has been identified in 20.0% (1723/8598) of European American chromosomes from a broad population by the NHLBI Exome Sequen cing Project (http://evs.gs.washington.edu/EVS; dbSNP rs4312063). -

-

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

-

Clinical Genetics, Academic Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Aug 15, 2013

Genetic Services Laboratory, University of Chicago

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:2 Other:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

-

ANO5 @LOVD

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Jul 12, 2017

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Miyoshi muscular dystrophy 3 Benign:1

Jul 14, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Limb-girdle muscular dystrophy, recessive Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

ANO5-Related Muscle Diseases Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Gnathodiaphyseal dysplasia Benign:1

Jul 14, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Autosomal recessive limb-girdle muscular dystrophy type 2L Benign:1

Jul 14, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Miyoshi myopathy Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

ANO5-related disorder Other:1

-

GenomeConnect - Invitae Patient Insights Network

Significance: not provided

Review Status: no classification provided

Collection Method: phenotyping only

Variant interpreted as Benign and reported on 11-11-2019 by Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	0.59
DANN	Benign	0.36

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: rs4312063; hg19: chr11-22242729; COSMIC: COSV61084691;