rs76850415

chr11-22279531-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_213599.3(ANO5):c.2521-13A>G variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0354 in 1,598,086 control chromosomes in the GnomAD database, including 1,120 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.026 (69 hom., cov: 32)
  • Exomes 𝑓: 0.036 (1051 hom.)
• Consequence: ANO5 NM_213599.3 splice_polypyrimidine_tract, intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: -1.57

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=-0.83).
• BP6: Variant 11-22279531-A-G is Benign according to our data. Variant chr11-22279531-A-G is described in ClinVar as [Benign]. Clinvar id is 96680.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-22279531-A-G is described in Lovd as [Benign]. Variant chr11-22279531-A-G is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0263 (3990/151922) while in subpopulation NFE AF= 0.0405 (2743/67790). AF 95% confidence interval is 0.0392. There are 69 homozygotes in gnomad4. There are 1861 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High AC in GnomAd at 3991 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ANO5	NM_213599.3	c.2521-13A>G		splice_polypyrimidine_tract_variant, intron_variant		ENST00000324559.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ANO5	ENST00000324559.9	c.2521-13A>G		splice_polypyrimidine_tract_variant, intron_variant		1	NM_213599.3	P2

Frequencies

GnomAD3 genomes AF: 0.0263 AC: 3991 AN: 151804 Hom.: 69 Cov.: 32

Gnomad AFR AF: 0.00795

Gnomad AMI AF: 0.0461

Gnomad AMR AF: 0.0204

Gnomad ASJ AF: 0.0450

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.0209

Gnomad FIN AF: 0.0203

Gnomad MID AF: 0.0222

Gnomad NFE AF: 0.0405

Gnomad OTH AF: 0.0414

GnomAD3 exomes AF: 0.0292 AC: 7270 AN: 248662 Hom.: 138 AF XY: 0.0303 AC XY: 4078 AN XY: 134534

Gnomad AFR exome AF: 0.00650

Gnomad AMR exome AF: 0.0165

Gnomad ASJ exome AF: 0.0439

Gnomad EAS exome AF: 0.0000545

Gnomad SAS exome AF: 0.0231

Gnomad FIN exome AF: 0.0221

Gnomad NFE exome AF: 0.0427

Gnomad OTH exome AF: 0.0339

GnomAD4 exome AF: 0.0364 AC: 52638 AN: 1446164 Hom.: 1051 Cov.: 31 AF XY: 0.0365 AC XY: 26274 AN XY: 720238

Gnomad4 AFR exome AF: 0.00614

Gnomad4 AMR exome AF: 0.0171

Gnomad4 ASJ exome AF: 0.0467

Gnomad4 EAS exome AF: 0.000126

Gnomad4 SAS exome AF: 0.0234

Gnomad4 FIN exome AF: 0.0233

Gnomad4 NFE exome AF: 0.0410

Gnomad4 OTH exome AF: 0.0330

GnomAD4 genome AF: 0.0263 AC: 3990 AN: 151922 Hom.: 69 Cov.: 32 AF XY: 0.0251 AC XY: 1861 AN XY: 74278

Gnomad4 AFR AF: 0.00792

Gnomad4 AMR AF: 0.0204

Gnomad4 ASJ AF: 0.0450

Gnomad4 EAS AF: 0.000386

Gnomad4 SAS AF: 0.0209

Gnomad4 FIN AF: 0.0203

Gnomad4 NFE AF: 0.0405

Gnomad4 OTH AF: 0.0405

Alfa AF: 0.0342 Hom.: 14

Bravo AF: 0.0260

Asia WGS AF: 0.00924 AC: 32 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 12, 2016	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. -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Mar 29, 2013	- -

Miyoshi muscular dystrophy 3 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Dec 05, 2021

- -

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. -

not provided Benign:1

Likely benign, no assertion criteria provided

clinical testing

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

-

- -

Gnathodiaphyseal dysplasia Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Dec 05, 2021

- -

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

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

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

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Dec 05, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
Cadd	Benign	2.3
Dann	Benign	0.55

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: rs76850415; hg19: chr11-22301077;