11-22236194-G-C

Variant names:

• chr11-22236194-G-C
• rs140903276
• NM_213599.3:c.680G>C

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 2P and 13B. PM1 BP4_Strong BP6 BS1 BS2

The NM_213599.3(ANO5):​c.680G>C​(p.Gly227Ala) variant causes a missense change. The variant allele was found at a frequency of 0.000555 in 1,613,114 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/22 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. G227S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0029 (3 hom., cov: 32)
  • Exomes 𝑓: 0.00031 (3 hom.)
• Consequence: ANO5 NM_213599.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:6
• Conservation: PhyloP100: 3.70
• 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):

• autosomal recessive limb-girdle muscular dystrophy

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• gnathodiaphyseal dysplasia

  Inheritance: AD Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), G2P
• autosomal recessive limb-girdle muscular dystrophy type 2L

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

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

ACMG classification

Our verdict: Benign. The variant received -11 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 7 uncertain in NM_213599.3
• BP4: Computational evidence support a benign effect (MetaRNN=0.007077068).
• BP6: Variant 11-22236194-G-C is Benign according to our data. Variant chr11-22236194-G-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 282496.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0029 (441/152212) while in subpopulation AFR AF = 0.0101 (421/41550). AF 95% confidence interval is 0.00933. There are 3 homozygotes in GnomAd4. There are 190 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 3 AR,AD 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ANO5	NM_213599.3	MANE Select	c.680G>C	p.Gly227Ala	missense	Exon 8 of 22	NP_998764.1
	ANO5	NM_001142649.2		c.677G>C	p.Gly226Ala	missense	Exon 8 of 22	NP_001136121.1
	ANO5	NM_001410963.1		c.638G>C	p.Gly213Ala	missense	Exon 7 of 21	NP_001397892.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ANO5	ENST00000324559.9	TSL:1 MANE Select	c.680G>C	p.Gly227Ala	missense	Exon 8 of 22	ENSP00000315371.9
	ANO5	ENST00000682341.1		c.638G>C	p.Gly213Ala	missense	Exon 7 of 21	ENSP00000508251.1
	ANO5	ENST00000684663.1		c.635G>C	p.Gly212Ala	missense	Exon 7 of 21	ENSP00000508009.1

Frequencies

GnomAD3 genomes AF: 0.00289 AC: 439 AN: 152094 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.0101

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: 0.0000588

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000761 AC: 191 AN: 250910 AF XY: 0.000583

Gnomad AFR exome AF: 0.0102

Gnomad AMR exome AF: 0.000608

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000265

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000311 AC: 454 AN: 1460902 Hom.: 3 Cov.: 30 AF XY: 0.000260 AC XY: 189 AN XY: 726804

African (AFR) AF: 0.0111 AC: 370 AN: 33436

American (AMR) AF: 0.000537 AC: 24 AN: 44678

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26108

East Asian (EAS) AF: 0.00 AC: 0 AN: 39560

South Asian (SAS) AF: 0.0000348 AC: 3 AN: 86244

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53386

Middle Eastern (MID) AF: 0.000174 AC: 1 AN: 5760

European-Non Finnish (NFE) AF: 0.0000216 AC: 24 AN: 1111386

Other (OTH) AF: 0.000530 AC: 32 AN: 60344

GnomAD4 genome AF: 0.00290 AC: 441 AN: 152212 Hom.: 3 Cov.: 32 AF XY: 0.00255 AC XY: 190 AN XY: 74426

African (AFR) AF: 0.0101 AC: 421 AN: 41550

American (AMR) AF: 0.000982 AC: 15 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3464

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10598

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

European-Non Finnish (NFE) AF: 0.0000588 AC: 4 AN: 67990

Other (OTH) AF: 0.000473 AC: 1 AN: 2114

Alfa AF: 0.000481 Hom.: 0

Bravo AF: 0.00315

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.00862 AC: 38

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000873 AC: 106

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.0000546

EpiControl AF: 0.00

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	2	not provided (3)
-	-	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	0.15
BayesDel_addAF	Benign	-0.52	T
BayesDel_noAF	Benign	-0.50
CADD	Benign	19
DANN	Benign	0.90
DEOGEN2	Benign	0.069	T
Eigen	Benign	0.032
Eigen_PC	Benign	0.056
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.82	T
M_CAP	Benign	0.081	D
MetaRNN	Benign	0.0071	T
MetaSVM	Benign	-0.55	T
MutationAssessor	Uncertain	2.0	M
PhyloP100		3.7
PrimateAI	Uncertain	0.48	T
PROVEAN	Uncertain	-2.5	D
REVEL	Benign	0.21
Sift	Benign	0.33	T
Sift4G	Benign	0.66	T
Polyphen		0.83	P
Vest4		0.51
MVP		0.53
MPC		0.32
ClinPred		0.027	T
GERP RS		4.8
Varity_R		0.16
gMVP		0.72
Mutation Taster		=91/9	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: rs140903276; hg19: chr11-22257740;