chr11-22227542-G-A

Variant names:

• chr11-22227542-G-A
• rs115750596
• NM_213599.3:c.604G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_213599.3(ANO5):​c.604G>A​(p.Glu202Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00187 in 1,613,342 control chromosomes in the GnomAD database, including 41 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). The gene ANO5 is included in the ClinGen Criteria Specification Registry.

• Frequency:
  • Genomes: 𝑓 0.0089 (20 hom., cov: 32)
  • Exomes 𝑓: 0.0011 (21 hom.)
• Consequence: ANO5 NM_213599.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:15
• Conservation: PhyloP100: 0.744
• Publications: 7 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0053126216).
• BP6: Variant 11-22227542-G-A is Benign according to our data. Variant chr11-22227542-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 263316.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00892 (1357/152064) while in subpopulation AFR AF = 0.031 (1287/41480). AF 95% confidence interval is 0.0296. There are 20 homozygotes in GnomAd4. There are 617 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 20 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.604G>A	p.Glu202Lys	missense	Exon 7 of 22	NP_998764.1	Q75V66
	ANO5	NM_001142649.2		c.601G>A	p.Glu201Lys	missense	Exon 7 of 22	NP_001136121.1
	ANO5	NM_001410963.1		c.562G>A	p.Glu188Lys	missense	Exon 6 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.604G>A	p.Glu202Lys	missense	Exon 7 of 22	ENSP00000315371.9	Q75V66
	ANO5	ENST00000682341.1		c.562G>A	p.Glu188Lys	missense	Exon 6 of 21	ENSP00000508251.1	A0A804HL91
	ANO5	ENST00000684663.1		c.559G>A	p.Glu187Lys	missense	Exon 6 of 21	ENSP00000508009.1	A0A804HKP2

Frequencies

GnomAD3 genomes AF: 0.00895 AC: 1360 AN: 151946 Hom.: 20 Cov.: 32

Gnomad AFR AF: 0.0312

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00217

Gnomad ASJ AF: 0.00260

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: 0.00719

GnomAD2 exomes AF: 0.00247 AC: 618 AN: 250550 AF XY: 0.00173

Gnomad AFR exome AF: 0.0317

Gnomad AMR exome AF: 0.00151

Gnomad ASJ exome AF: 0.00159

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000283

Gnomad OTH exome AF: 0.000656

GnomAD4 exome AF: 0.00113 AC: 1655 AN: 1461278 Hom.: 21 Cov.: 32 AF XY: 0.00101 AC XY: 734 AN XY: 726936

African (AFR) AF: 0.0344 AC: 1151 AN: 33430

American (AMR) AF: 0.00146 AC: 65 AN: 44592

Ashkenazi Jewish (ASJ) AF: 0.00157 AC: 41 AN: 26112

East Asian (EAS) AF: 0.00 AC: 0 AN: 39680

South Asian (SAS) AF: 0.00 AC: 0 AN: 86242

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53396

Middle Eastern (MID) AF: 0.00417 AC: 24 AN: 5760

European-Non Finnish (NFE) AF: 0.000205 AC: 228 AN: 1111708

Other (OTH) AF: 0.00242 AC: 146 AN: 60358

GnomAD4 genome AF: 0.00892 AC: 1357 AN: 152064 Hom.: 20 Cov.: 32 AF XY: 0.00830 AC XY: 617 AN XY: 74306

African (AFR) AF: 0.0310 AC: 1287 AN: 41480

American (AMR) AF: 0.00216 AC: 33 AN: 15258

Ashkenazi Jewish (ASJ) AF: 0.00260 AC: 9 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5166

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10584

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

European-Non Finnish (NFE) AF: 0.000191 AC: 13 AN: 67976

Other (OTH) AF: 0.00712 AC: 15 AN: 2108

Alfa AF: 0.00342 Hom.: 7

Bravo AF: 0.00960

ESP6500AA AF: 0.0340 AC: 150

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.00285 AC: 346

Asia WGS AF: 0.00231 AC: 8 AN: 3478

EpiCase AF: 0.000327

EpiControl AF: 0.000356

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	6	not specified (6)
-	-	4	not provided (4)
-	-	1	ANO5-Related Muscle Diseases (1)
-	-	1	Autosomal recessive limb-girdle muscular dystrophy type 2L (1)
-	-	1	Gnathodiaphyseal dysplasia (1)
-	-	1	Gnathodiaphyseal dysplasia;C1969785:Autosomal recessive limb-girdle muscular dystrophy type 2L (1)
-	-	1	Miyoshi muscular dystrophy 3 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.071
BayesDel_addAF	Benign	-0.61	T
BayesDel_noAF	Benign	-0.62
CADD	Benign	18
DANN	Benign	0.96
DEOGEN2	Benign	0.040	T
Eigen	Benign	-0.43
Eigen_PC	Benign	-0.24
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Uncertain	0.88	D
MetaRNN	Benign	0.0053	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.3	L
PhyloP100		0.74
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-1.6	N
REVEL	Benign	0.062
Sift	Benign	0.97	T
Sift4G	Benign	0.59	T
Polyphen		0.0040	B
Vest4		0.69
MVP		0.18
MPC		0.10
ClinPred		0.0059	T
GERP RS		4.8
Varity_R		0.27
gMVP		0.47
Mutation Taster		=87/13	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.13		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: rs115750596; hg19: chr11-22249088;