11-22250758-C-G

Variant names:

• chr11-22250758-C-G
• rs541372136
• NM_213599.3:c.1031C>G

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 2P and 6B. PM1 BP4_Strong BP6 BS2_Supporting

The NM_213599.3(ANO5):​c.1031C>G​(p.Pro344Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000178 in 1,613,938 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). The gene ANO5 is included in the ClinGen Criteria Specification Registry.

• Frequency:
  • Genomes: 𝑓 0.00012 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00018 (3 hom.)
• Consequence: ANO5 NM_213599.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:2
• Conservation: PhyloP100: 1.74
• Publications: 0 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: ClinGen, Labcorp Genetics (formerly Invitae), G2P, Orphanet
• 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, Labcorp Genetics (formerly Invitae), Orphanet
• 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: Likely_benign. The variant received -4 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, 15 uncertain in NM_213599.3
• BP4: Computational evidence support a benign effect (MetaRNN=0.0063638985).
• BP6: Variant 11-22250758-C-G is Benign according to our data. Variant chr11-22250758-C-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 288517.
• BS2: High Homozygotes in GnomAdExome4 at 3 AD,AR geneVariant has number of homozygotes lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

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.1031C>G	p.Pro344Arg	missense	Exon 11 of 22	NP_998764.1	Q75V66
	ANO5	NM_001142649.2		c.1028C>G	p.Pro343Arg	missense	Exon 11 of 22	NP_001136121.1
	ANO5	NM_001410963.1		c.989C>G	p.Pro330Arg	missense	Exon 10 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.1031C>G	p.Pro344Arg	missense	Exon 11 of 22	ENSP00000315371.9	Q75V66
	ANO5	ENST00000682341.1		c.989C>G	p.Pro330Arg	missense	Exon 10 of 21	ENSP00000508251.1	A0A804HL91
	ANO5	ENST00000684663.1		c.986C>G	p.Pro329Arg	missense	Exon 10 of 21	ENSP00000508009.1	A0A804HKP2

Frequencies

GnomAD3 genomes AF: 0.000112 AC: 17 AN: 152104 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00352

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000335 AC: 84 AN: 251012 AF XY: 0.000450

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS 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: 0.000184 AC: 269 AN: 1461716 Hom.: 3 Cov.: 32 AF XY: 0.000276 AC XY: 201 AN XY: 727164

African (AFR) AF: 0.00 AC: 0 AN: 33470

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26128

East Asian (EAS) AF: 0.00 AC: 0 AN: 39678

South Asian (SAS) AF: 0.00301 AC: 260 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53412

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111898

Other (OTH) AF: 0.000132 AC: 8 AN: 60386

GnomAD4 genome AF: 0.000118 AC: 18 AN: 152222 Hom.: 0 Cov.: 32 AF XY: 0.000202 AC XY: 15 AN XY: 74420

African (AFR) AF: 0.00 AC: 0 AN: 41542

American (AMR) AF: 0.00 AC: 0 AN: 15288

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5170

South Asian (SAS) AF: 0.00373 AC: 18 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10600

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68010

Other (OTH) AF: 0.00 AC: 0 AN: 2114

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000189

ExAC AF: 0.000387 AC: 47

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.38	T
BayesDel_noAF	Benign	-0.33
CADD	Uncertain	24
DANN	Benign	0.97
DEOGEN2	Benign	0.30	T
Eigen	Benign	-0.021
Eigen_PC	Benign	0.085
FATHMM_MKL	Benign	0.74	D
LIST_S2	Benign	0.82	T
M_CAP	Benign	0.051	D
MetaRNN	Benign	0.0064	T
MetaSVM	Benign	-0.43	T
MutationAssessor	Benign	1.8	L
PhyloP100		1.7
PrimateAI	Benign	0.43	T
PROVEAN	Pathogenic	-5.9	D
REVEL	Benign	0.15
Sift	Uncertain	0.019	D
Sift4G	Benign	0.17	T
Polyphen		0.11	B
Vest4		0.36
MutPred		0.40		Gain of solvent accessibility (P = 0.0216)
MVP		0.82
MPC		0.23
ClinPred		0.26	T
GERP RS		3.5
Varity_R		0.33
gMVP		0.67
Mutation Taster		=82/18	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

Other links and lift over

dbSNP: rs541372136; hg19: chr11-22272304;