rs144048656

chr11-22274589-G-Achr11-22274589-G-C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6 BP7 BS1 BS2

The NM_213599.3(ANO5):c.2256G>A(p.Thr752=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00101 in 1,597,938 control chromosomes in the GnomAD database, including 19 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00061 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0010 (19 hom.)
• Consequence: ANO5 NM_213599.3 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:10
• Conservation: PhyloP100: 0.264

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.58).
• BP6: Variant 11-22274589-G-A is Benign according to our data. Variant chr11-22274589-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 285552.We mark this variant Likely_benign, oryginal submissions are: {Benign=6, Likely_benign=2, Uncertain_significance=1}. Variant chr11-22274589-G-A is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=0.264 with no splicing effect.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.000612 (92/150212) while in subpopulation SAS AF= 0.0118 (56/4756). AF 95% confidence interval is 0.00931. There are 0 homozygotes in gnomad4. There are 54 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High AC in GnomAd at 91 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ANO5	NM_213599.3	c.2256G>A	p.Thr752=	synonymous_variant	20/22	ENST00000324559.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ANO5	ENST00000324559.9	c.2256G>A	p.Thr752=	synonymous_variant	20/22	1	NM_213599.3	P2

Frequencies

GnomAD3 genomes AF: 0.000606 AC: 91 AN: 150100 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000200

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0116

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000459

Gnomad OTH AF: 0.000969

GnomAD3 exomes AF: 0.00168 AC: 416 AN: 248348 Hom.: 8 AF XY: 0.00221 AC XY: 297 AN XY: 134236

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000175

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000546

Gnomad SAS exome AF: 0.0114

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000507

Gnomad OTH exome AF: 0.000996

GnomAD4 exome AF: 0.00105 AC: 1518 AN: 1447726 Hom.: 19 Cov.: 33 AF XY: 0.00139 AC XY: 999 AN XY: 717998

Gnomad4 AFR exome AF: 0.0000601

Gnomad4 AMR exome AF: 0.000249

Gnomad4 ASJ exome AF: 0.0000388

Gnomad4 EAS exome AF: 0.0000509

Gnomad4 SAS exome AF: 0.0113

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000396

Gnomad4 OTH exome AF: 0.00117

GnomAD4 genome AF: 0.000612 AC: 92 AN: 150212 Hom.: 0 Cov.: 32 AF XY: 0.000738 AC XY: 54 AN XY: 73154

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.000200

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.0118

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000459

Gnomad4 OTH AF: 0.000960

Alfa AF: 0.000247 Hom.: 0

Bravo AF: 0.000298

Asia WGS AF: 0.00346 AC: 12 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:10

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:4

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Nov 01, 2018	- -
Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 08, 2020	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Feb 15, 2023	- -

not specified Benign:2

Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jan 29, 2016	- -

ANO5-Related Muscle Diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

Miyoshi muscular dystrophy 3 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Dec 05, 2021

- -

Gnathodiaphyseal dysplasia Benign:1

Likely 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

Dec 28, 2023

- -

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	-0.58
Cadd	Benign	6.0
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: rs144048656; hg19: chr11-22296135; COSMIC: COSV61083537;