rs200631556

chr11-22272895-C-G

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM1 BP4_Moderate BS2

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
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:8 B:1
• Conservation: PhyloP100: 7.90

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 Likely_benign. Variant got -4 ACMG points.

• PM1: In a topological_domain Cytoplasmic (size 31) in uniprot entity ANO5_HUMAN there are 6 pathogenic changes around while only 1 benign (86%) in NM_213599.3
• BP4: Computational evidence support a benign effect (MetaRNN=0.19104081).
• BS2: High AC in GnomAd at 137 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ANO5	NM_213599.3	c.2141C>G	p.Thr714Ser	missense_variant	19/22	ENST00000324559.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ANO5	ENST00000324559.9	c.2141C>G	p.Thr714Ser	missense_variant	19/22	1	NM_213599.3	P2

Frequencies

GnomAD3 genomes AF: 0.000901 AC: 137 AN: 152122 Hom.: 0 Cov.: 32

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

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

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

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:1 Uncertain:8 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:1 Uncertain:5

Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Sep 12, 2018	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Nov 22, 2021	Identified in individuals with limb-girdle muscular dystrophy and suspected limb-girdle muscular dystrophy 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 (Savarese et al., 2015; Nallamilli et al., 2018); Reported previously in individuals with muscular dystrophy, suspected LGMD, and/or unspecified neuromuscular disorder with myopathic changes on biopsy who harborded another ANO5 pathogenic variant; however, segregation analysis was not provided and functional characterization of the variant was not performed (Penttila et al., 2012; Nallamilli et al., 2018; Gonzalez-Quereda et al., 2020).; 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, 27884173, 30564623, 32403337, 22402862, 25891276) -
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. -
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. -
Likely pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2024	ANO5: PM3:Strong, PM2 -

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

Invitae

Jan 26, 2024

- -

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
MutationTaster	Benign	1.0	D
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

Other links and lift over

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