11-22279544-C-G

Position:

chr11-22279544-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 5P and 1B. PP3_StrongPP5BS2_Supporting

The NM_213599.3(ANO5):c.2521C>G(p.His841Asp) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000672 in 1,607,580 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000033 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000071 ( 0 hom. )

Consequence

ANO5
NM_213599.3 missense, splice_region

Scores

Splicing: ADA: 0.9749

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:6U:2

Conservation

PhyloP100: 7.49

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.969

PP5

Variant 11-22279544-C-G is Pathogenic according to our data. Variant chr11-22279544-C-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 195705.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=4, Uncertain_significance=2, Pathogenic=2}. Variant chr11-22279544-C-G is described in Lovd as [Likely_pathogenic].

BS2

High AC in GnomAd4 at 5 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.2521C>G	p.His841Asp	missense_variant, splice_region_variant	22/22	ENST00000324559.9	NP_998764.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ANO5	ENST00000324559.9 linkuse as main transcript	c.2521C>G	p.His841Asp	missense_variant, splice_region_variant	22/22	1	NM_213599.3	ENSP00000315371	P2

Frequencies

GnomAD3 genomes

AF:

0.0000329

AC:

AN:

151828

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000737

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000481

AC:

AN:

249618

Hom.:

AF XY:

0.0000519

AC XY:

AN XY:

134988

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000873

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000712

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000708

AC:

103

AN:

1455752

Hom.:

Cov.:

AF XY:

0.0000621

AC XY:

AN XY:

724538

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000897

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000822

Gnomad4 OTH exome

AF:

0.0000997

GnomAD4 genome

AF:

0.0000329

AC:

AN:

151828

Hom.:

Cov.:

AF XY:

0.0000539

AC XY:

AN XY:

74146

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000737

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000113

Hom.:

Bravo

AF:

0.0000491

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00

AC:

ExAC

AF:

0.0000165

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.000109

EpiControl

AF:

0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:6Uncertain:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Pathogenic:4

Likely pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jul 20, 2021	The frequency of this variant in the general population is consistent with pathogenicity (http://gnomad.broadinstitute.org). This variant segregates with disease in at least one family. Computational tools predict that this variant is damaging. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Sep 01, 2016	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Sep 07, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jul 07, 2015	The H841D missense variant in the ANO5 gene has been reported previously in an individual with limb-girdle muscular dystrophy type 2L also known as, anoctaminopathy, who was heterozygous for this change and did not have another identifiable variant (Sarkozy et al., 2013). H841D was subsequently identified in an individual with limb-girdle muscular dystrophy type 2L who was compound heterozygous for H841D and another ANO5 variant(Leung et al., 2014). The H841D pathogenic variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. Additionally, in silico analysis predicts this sequence change is probably damaging to the protein structure/function, and other missense variants in nearby residues (M833K, M839R) have been reported in the Human Gene Mutation Database in association with ANO5-related disorders (Stenson et al., 2014), supporting the functional importance of this region of the protein. Given the available evidence, we interpret H841D as a pathogenic variant. -

Autosomal recessive limb-girdle muscular dystrophy

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Aug 28, 2023

Variant summary: ANO5 c.2521C>G (p.His841Asp) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. Consensus agreement among computation tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 4.8e-05 in 249618 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in ANO5 causing Limb-Girdle Muscular Dystrophy, Autosomal Recessive (4.8e-05 vs 0.0047), allowing no conclusion about variant significance. c.2521C>G has been reported in the literature in multiple compound heterozygous individuals affected with Limb-Girdle Muscular Dystrophy, Autosomal Recessive (e.g., Leung_2014, Jarmula_2019, Gonzalez-Quereda_2020, Segui_2020, Topf_2020). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 32403337, 31395899, 24022920, 23606453, 32528171, 32399949). Seven submitters have reported clinical-significance assessments for this variant to ClinVar after 2014. Multiple submitters reported the variant with conflicting assessments (pathogenic, n = 2; likely pathogenic, n = 3, uncertain significance, n = 2). Based on the evidence outlined above, the variant was classified as likely pathogenic. -

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

Nov 16, 2023

This sequence change replaces histidine, which is basic and polar, with aspartic acid, which is acidic and polar, at codon 841 of the ANO5 protein (p.His841Asp). This variant is present in population databases (rs781027702, gnomAD 0.009%). This missense change has been observed in individual(s) with clinical features of autosomal recessive limb-girdle muscular dystrophy (PMID: 24022920, 31395899, 32403337). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 195705). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. For these reasons, this variant has been classified as Pathogenic. -

ANO5-related disorder

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 10, 2019

The ANO5 c.2521C>G (p.His841Asp) missense variant has been reported in two studies in which it is found in a total of three patients, including one individual with suspected limb-girdle muscular dystrophy type 2L in a heterozygous state (Sarkozy et al. 2013) and two affected siblings in a compound heterozygous state (Leung et al. 2014). The p.His841Asp variant was observed in cis with a second variant that was predicted to be benign and in trans with a third known pathogenic variant in the two siblings. In addition, the p.His841Asp variant was present in cis with the second variant in a heterozygous state in one of the sibling's unaffected children (Leung et al. 2014). Control data are unavailable for this variant which is reported at a frequency of 0.00009 in the Latino population of the Genome Aggregation Database. Based on the evidence, the ANO5 p.His841Asp variant is classified as a variant of unknown significance but suspicious for pathogenicity for ANO5-Related Disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -

Limb-girdle muscular dystrophy

Uncertain:1

Uncertain significance, criteria provided, single submitter

research

Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard

May 29, 2020

The p.His841Asp variant in ANO5 was identified by our study in 1 individual with limb-girdle muscular dystrophy, along with a variant of uncertain significance. The variant in ANO5 has been reported in 4 individuals with limb-girdle muscular dystrophy, including the one from our study (PMID: 31395899, 24022920, 23606453). The presence of this variant in combination with a reported pathogenic variant, and in an individual with limb-girdle muscular dystrophy increases the likelihood that the p.His841Asp variant is pathogenic (Variation ID: 424764; PMID: 24022920). This variant has been identified in 0.009% (3/34378) of Latino chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP (rs781027702). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. This variant has also been reported in ClinVar as pathogenic by GeneDx, likley pathogenic by Invitae and EGL Genetic Diagnostics, Eurofins Clinical Diagnostics, and as a variant of uncertain significance by Illumina Clinical Services Laboratory, Illumina (Variation ID:195705). Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, while there is some suspicion for a pathogenic role, the clinical significance of this variant is uncertain. ACMG/AMP Criteria applied: PM2, PP3, PM3 (Richards 2015). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.98

BayesDel_addAF

Pathogenic

0.24

BayesDel_noAF

Pathogenic

0.31

CADD

Pathogenic

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.59

Eigen

Pathogenic

0.94

Eigen_PC

Pathogenic

0.87

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Uncertain

0.97

M_CAP

Uncertain

0.21

MetaRNN

Pathogenic

0.97

MetaSVM

Uncertain

0.43

MutationAssessor

Pathogenic

4.0

MutationTaster

Benign

1.0

PrimateAI

Uncertain

0.76

PROVEAN

Pathogenic

-8.3

REVEL

Pathogenic

0.82

Sift

Uncertain

0.0010

Sift4G

Uncertain

0.016

Polyphen

1.0

Vest4

0.89

MVP

0.86

MPC

0.55

ClinPred

1.0

GERP RS

5.8

Varity_R

0.82

gMVP

0.95

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

0.97

dbscSNV1_RF

Benign

0.68

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