Genetic Variant NM_213599.3:c.-136G>C (chr11-22193357-G-C) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_213599.3(ANO5):c.-136G>C variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.826 in 151,762 control chromosomes in the GnomAD database, including 52,288 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.83 ( 52288 hom., cov: 29)

Exomes 𝑓: 0.80 ( 439941 hom. )

Failed GnomAD Quality Control

Consequence

ANO5
NM_213599.3 5_prime_UTR

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:9O:1

Conservation

PhyloP100: -1.24

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 Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.96).

BP6

Variant 11-22193357-G-C is Benign according to our data. Variant chr11-22193357-G-C is described in ClinVar as [Benign]. Clinvar id is 140544.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-22193357-G-C is described in Lovd as [Benign].

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 link	c.-136G>C		5_prime_UTR_variant	Exon 1 of 22	ENST00000324559.9	NP_998764.1	Q75V66

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ANO5	ENST00000324559 link	c.-136G>C		5_prime_UTR_variant	Exon 1 of 22	1	NM_213599.3	ENSP00000315371.9		Q75V66

Frequencies

GnomAD3 genomes

AF:

0.826

AC:

125232

AN:

151640

Hom.:

52231

Cov.:

show subpopulations

Gnomad AFR

AF:

0.930

Gnomad AMI

AF:

0.877

Gnomad AMR

AF:

0.719

Gnomad ASJ

AF:

0.753

Gnomad EAS

AF:

0.556

Gnomad SAS

AF:

0.805

Gnomad FIN

AF:

0.819

Gnomad MID

AF:

0.804

Gnomad NFE

AF:

0.813

Gnomad OTH

AF:

0.813

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.799

AC:

1094554

AN:

1370602

Hom.:

439941

Cov.:

AF XY:

0.799

AC XY:

538657

AN XY:

674350

show subpopulations

Gnomad4 AFR exome

AF:

0.936

Gnomad4 AMR exome

AF:

0.627

Gnomad4 ASJ exome

AF:

0.755

Gnomad4 EAS exome

AF:

0.518

Gnomad4 SAS exome

AF:

0.804

Gnomad4 FIN exome

AF:

0.809

Gnomad4 NFE exome

AF:

0.810

Gnomad4 OTH exome

AF:

0.795

GnomAD4 genome

AF:

0.826

AC:

125352

AN:

151762

Hom.:

52288

Cov.:

AF XY:

0.823

AC XY:

61018

AN XY:

74140

show subpopulations

Gnomad4 AFR

AF:

0.930

Gnomad4 AMR

AF:

0.719

Gnomad4 ASJ

AF:

0.753

Gnomad4 EAS

AF:

0.556

Gnomad4 SAS

AF:

0.806

Gnomad4 FIN

AF:

0.819

Gnomad4 NFE

AF:

0.813

Gnomad4 OTH

AF:

0.814

Alfa

AF:

0.824

Hom.:

6063

Bravo

AF:

0.815

ClinVar

Significance: Benign

Submissions summary: Benign:9Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2Other: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

- -

Jun 14, 2018

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. -

Miyoshi muscular dystrophy 3

Benign:1

Jul 14, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified

Benign:1

Apr 12, 2016

Eurofins Ntd Llc (ga)

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 12, 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

- -

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

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.96

CADD

Benign

0.34

DANN

Benign

0.48

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