rs35804601

chr11-22250822-A-G

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_213599.3(ANO5):c.1095A>G(p.Leu365=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000319 in 1,614,020 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0017 (3 hom., cov: 32)
  • Exomes 𝑓: 0.00017 (0 hom.)
• Consequence: ANO5 NM_213599.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7 O:1
• Conservation: PhyloP100: -1.69

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BP6: Variant 11-22250822-A-G is Benign according to our data. Variant chr11-22250822-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 140546.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.69 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00171 (261/152298) while in subpopulation AFR AF= 0.00616 (256/41560). AF 95% confidence interval is 0.00554. There are 3 homozygotes in gnomad4. There are 107 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High AC in GnomAd at 261 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ANO5	NM_213599.3	c.1095A>G	p.Leu365=	synonymous_variant	11/22	ENST00000324559.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ANO5	ENST00000324559.9	c.1095A>G	p.Leu365=	synonymous_variant	11/22	1	NM_213599.3	P2

Frequencies

GnomAD3 genomes AF: 0.00172 AC: 261 AN: 152180 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.00618

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

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: 0.0000147

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000458 AC: 115 AN: 251092 Hom.: 0 AF XY: 0.000324 AC XY: 44 AN XY: 135682

Gnomad AFR exome AF: 0.00664

Gnomad AMR exome AF: 0.000145

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000327

GnomAD4 exome AF: 0.000174 AC: 254 AN: 1461722 Hom.: 0 Cov.: 32 AF XY: 0.000153 AC XY: 111 AN XY: 727164

Gnomad4 AFR exome AF: 0.00672

Gnomad4 AMR exome AF: 0.000134

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000360

Gnomad4 OTH exome AF: 0.000315

GnomAD4 genome AF: 0.00171 AC: 261 AN: 152298 Hom.: 3 Cov.: 32 AF XY: 0.00144 AC XY: 107 AN XY: 74472

Gnomad4 AFR AF: 0.00616

Gnomad4 AMR AF: 0.000196

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.00101 Hom.: 0

Bravo AF: 0.00203

Asia WGS AF: 0.000578 AC: 2 AN: 3476

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7 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	-	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 01, 2021	- -

Miyoshi muscular dystrophy 3 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Dec 05, 2021

- -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Feb 26, 2015

- -

ANO5-Related Muscle Diseases Benign:1

Likely 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

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 11, 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	-0.79
Cadd	Benign	1.5
Dann	Benign	0.68

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: rs35804601; hg19: chr11-22272368;