11-22193357-G-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8 O:1
• Conservation: PhyloP100: -1.24

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 -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/exons	MANE	UniProt
ANO5	NM_213599.3	c.-136G>C		5_prime_UTR_variant	1/22	ENST00000324559.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ANO5	ENST00000324559.9	c.-136G>C		5_prime_UTR_variant	1/22	1	NM_213599.3	P2

Frequencies

GnomAD3 genomes AF: 0.826 AC: 125232 AN: 151640 Hom.: 52231 Cov.: 29

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.: 63 AF XY: 0.799 AC XY: 538657 AN XY: 674350

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.: 29 AF XY: 0.823 AC XY: 61018 AN XY: 74140

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:8 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1 Other:1

not provided, no classification provided	literature only	ANO5 @LOVD	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 14, 2018	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

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 14, 2021

- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Apr 12, 2016

- -

Limb-Girdle Muscular Dystrophy, Recessive Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

ANO5-Related Muscle Diseases Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

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

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 14, 2021

- -

Miyoshi myopathy Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

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

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 14, 2021

- -

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

Other links and lift over

dbSNP: rs12792259; hg19: chr11-22214903; COSMIC: COSV61083375;