NM_213599.3:c.259G>A

Variant names:

• chr11-22221175-G-A
• rs34994927
• NM_213599.3:c.259G>A
• ANO5 p.Val87Ile

Variant summary

Our verdict is

Benign

-9 Benign

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

. The variant received -9 ACMG points: 2P and 11B. PM1BP4_ModerateBP6BS1BS2

The NM_213599.3(ANO5):​c.259G>A​(p.Val87Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000691 in 1,611,662 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V87F) has been classified as Uncertain significance. The gene ANO5 is included in the ClinGen Criteria Specification Registry.

• Frequency:
  • Genomes: 𝑓 0.0030 (3 hom., cov: 32)
  • Exomes 𝑓: 0.00045 (3 hom.)
• Consequence: ANO5 NM_213599.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:7
• Conservation: PhyloP100: 2.62
• Publications: 10 publications found

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 Gene-Disease associations (from GenCC):

• gnathodiaphyseal dysplasia

  Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: PanelApp Australia, Orphanet, ClinGen, G2P, Labcorp Genetics (formerly Invitae)
• autosomal recessive limb-girdle muscular dystrophy

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• autosomal recessive limb-girdle muscular dystrophy type 2L

  Inheritance: AR Classification: STRONG, SUPPORTIVE, LIMITED Submitted by: G2P, PanelApp Australia, Orphanet, Labcorp Genetics (formerly Invitae)
• Miyoshi muscular dystrophy 3

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

Specifications for ANO5 are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Our verdict: Benign. The variant received -9 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 14 uncertain in NM_213599.3
• BP4: Computational evidence support a benign effect (REVEL=0.031).
• BP6: Variant 11-22221175-G-A is Benign according to our data. Variant chr11-22221175-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 282497.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00299 (454/152006) while in subpopulation AFR AF = 0.0102 (425/41514). AF 95% confidence interval is 0.00943. There are 3 homozygotes in GnomAd4. There are 195 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 3 AD,AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_213599.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ANO5	NM_213599.3	MANE Select	c.259G>A	p.Val87Ile	missense	Exon 5 of 22	NP_998764.1	Q75V66
	ANO5	NM_001142649.2		c.256G>A	p.Val86Ile	missense	Exon 5 of 22	NP_001136121.1
	ANO5	NM_001410963.1		c.217G>A	p.Val73Ile	missense	Exon 4 of 21	NP_001397892.1	A0A804HL91

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ANO5	ENST00000324559.9	TSL:1 MANE Select	c.259G>A	p.Val87Ile	missense	Exon 5 of 22	ENSP00000315371.9	Q75V66
	ANO5	ENST00000682341.1		c.217G>A	p.Val73Ile	missense	Exon 4 of 21	ENSP00000508251.1	A0A804HL91
	ANO5	ENST00000684663.1		c.214G>A	p.Val72Ile	missense	Exon 4 of 21	ENSP00000508009.1	A0A804HKP2

Frequencies

GnomAD3 genomes AF: 0.00298 AC: 452 AN: 151888 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.0102

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00105

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: 0.000191

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000868 AC: 217 AN: 250110 AF XY: 0.000718

Gnomad AFR exome AF: 0.0102

Gnomad AMR exome AF: 0.000611

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000545

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000239

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000451 AC: 659 AN: 1459656 Hom.: 3 Cov.: 29 AF XY: 0.000395 AC XY: 287 AN XY: 726172

African (AFR) AF: 0.0112 AC: 375 AN: 33370

American (AMR) AF: 0.000539 AC: 24 AN: 44548

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26066

East Asian (EAS) AF: 0.0000758 AC: 3 AN: 39552

South Asian (SAS) AF: 0.0000464 AC: 4 AN: 86206

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53326

Middle Eastern (MID) AF: 0.000174 AC: 1 AN: 5748

European-Non Finnish (NFE) AF: 0.000195 AC: 217 AN: 1110594

Other (OTH) AF: 0.000581 AC: 35 AN: 60246

GnomAD4 genome AF: 0.00299 AC: 454 AN: 152006 Hom.: 3 Cov.: 32 AF XY: 0.00263 AC XY: 195 AN XY: 74280

African (AFR) AF: 0.0102 AC: 425 AN: 41514

American (AMR) AF: 0.000984 AC: 15 AN: 15244

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5154

South Asian (SAS) AF: 0.00 AC: 0 AN: 4820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10586

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000191 AC: 13 AN: 67902

Other (OTH) AF: 0.000473 AC: 1 AN: 2112

Alfa AF: 0.000934 Hom.: 2

Bravo AF: 0.00329

Asia WGS AF: 0.000867 AC: 3 AN: 3476

EpiCase AF: 0.000109

EpiControl AF: 0.000237

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	3	not provided (4)
-	-	1	ANO5-Related Muscle Diseases (1)
-	-	1	Gnathodiaphyseal dysplasia (1)
-	-	1	Gnathodiaphyseal dysplasia;C1969785:Autosomal recessive limb-girdle muscular dystrophy type 2L (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.072
BayesDel_addAF	Benign	-0.53	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	17
DANN	Benign	0.85
DEOGEN2	Benign	0.083	T
Eigen	Benign	-0.51
Eigen_PC	Benign	-0.43
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.67	T
M_CAP	Benign	0.029	D
MetaRNN	Benign	0.010	T
MetaSVM	Benign	-0.85	T
MutationAssessor	Benign	0.83	L
PhyloP100		2.6
PrimateAI	Benign	0.26	T
PROVEAN	Benign	-0.60	N
REVEL	Benign	0.031
Sift	Benign	0.47	T
Sift4G	Benign	0.44	T
Varity_R		0.069
gMVP		0.18
Mutation Taster		=88/12	polymorphism

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs34994927;

hg19: chr11-22242721;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline