chr11-22250324-A-T

Variant names:

• chr11-22250324-A-T
• rs7481951
• NM_213599.3:c.966A>T

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 2P and 20B. PM1 BP4_Strong BP6_Very_Strong BA1

The NM_213599.3(ANO5):​c.966A>T​(p.Leu322Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.54 in 1,612,376 control chromosomes in the GnomAD database, including 247,717 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. L322L) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.44 (17544 hom., cov: 32)
  • Exomes 𝑓: 0.55 (230173 hom.)
• Consequence: ANO5 NM_213599.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:18 O:1
• Conservation: PhyloP100: 0.00100
• Publications: 50 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

Our verdict: Benign. The variant received -18 ACMG points.

• PM1: In a topological_domain Extracellular (size 59) in uniprot entity ANO5_HUMAN there are 7 pathogenic changes around while only 2 benign (78%) in NM_213599.3
• BP4: Computational evidence support a benign effect (MetaRNN=2.8172135E-4).
• BP6: Variant 11-22250324-A-T is Benign according to our data. Variant chr11-22250324-A-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 96687.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.588 is higher than 0.05.

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.966A>T	p.Leu322Phe	missense	Exon 10 of 22	NP_998764.1	Q75V66
	ANO5	NM_001142649.2		c.963A>T	p.Leu321Phe	missense	Exon 10 of 22	NP_001136121.1
	ANO5	NM_001410963.1		c.924A>T	p.Leu308Phe	missense	Exon 9 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.966A>T	p.Leu322Phe	missense	Exon 10 of 22	ENSP00000315371.9	Q75V66
	ANO5	ENST00000682341.1		c.924A>T	p.Leu308Phe	missense	Exon 9 of 21	ENSP00000508251.1	A0A804HL91
	ANO5	ENST00000684663.1		c.921A>T	p.Leu307Phe	missense	Exon 9 of 21	ENSP00000508009.1	A0A804HKP2

Frequencies

GnomAD3 genomes AF: 0.441 AC: 66910 AN: 151890 Hom.: 17535 Cov.: 32

Gnomad AFR AF: 0.164

Gnomad AMI AF: 0.559

Gnomad AMR AF: 0.415

Gnomad ASJ AF: 0.609

Gnomad EAS AF: 0.199

Gnomad SAS AF: 0.499

Gnomad FIN AF: 0.594

Gnomad MID AF: 0.566

Gnomad NFE AF: 0.593

Gnomad OTH AF: 0.486

GnomAD2 exomes AF: 0.478 AC: 119591 AN: 250046 AF XY: 0.496

Gnomad AFR exome AF: 0.157

Gnomad AMR exome AF: 0.298

Gnomad ASJ exome AF: 0.602

Gnomad EAS exome AF: 0.179

Gnomad FIN exome AF: 0.590

Gnomad NFE exome AF: 0.586

Gnomad OTH exome AF: 0.525

GnomAD4 exome AF: 0.550 AC: 803860 AN: 1460368 Hom.: 230173 Cov.: 43 AF XY: 0.552 AC XY: 400941 AN XY: 726446

African (AFR) AF: 0.152 AC: 5084 AN: 33444

American (AMR) AF: 0.312 AC: 13916 AN: 44652

Ashkenazi Jewish (ASJ) AF: 0.611 AC: 15954 AN: 26106

East Asian (EAS) AF: 0.153 AC: 6075 AN: 39602

South Asian (SAS) AF: 0.507 AC: 43723 AN: 86186

European-Finnish (FIN) AF: 0.581 AC: 30975 AN: 53326

Middle Eastern (MID) AF: 0.579 AC: 3321 AN: 5732

European-Non Finnish (NFE) AF: 0.588 AC: 653307 AN: 1111002

Other (OTH) AF: 0.522 AC: 31505 AN: 60318

GnomAD4 genome AF: 0.440 AC: 66928 AN: 152008 Hom.: 17544 Cov.: 32 AF XY: 0.440 AC XY: 32712 AN XY: 74276

African (AFR) AF: 0.164 AC: 6808 AN: 41496

American (AMR) AF: 0.415 AC: 6335 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.609 AC: 2110 AN: 3466

East Asian (EAS) AF: 0.199 AC: 1028 AN: 5172

South Asian (SAS) AF: 0.501 AC: 2416 AN: 4824

European-Finnish (FIN) AF: 0.594 AC: 6260 AN: 10546

Middle Eastern (MID) AF: 0.582 AC: 171 AN: 294

European-Non Finnish (NFE) AF: 0.593 AC: 40262 AN: 67926

Other (OTH) AF: 0.488 AC: 1030 AN: 2110

Alfa AF: 0.549 Hom.: 17185

Bravo AF: 0.407

TwinsUK AF: 0.576 AC: 2137

ALSPAC AF: 0.585 AC: 2254

ESP6500AA AF: 0.180 AC: 794

ESP6500EA AF: 0.586 AC: 5041

ExAC AF: 0.480 AC: 58309

Asia WGS AF: 0.325 AC: 1136 AN: 3476

EpiCase AF: 0.581

EpiControl AF: 0.584

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	10	not specified (10)
-	-	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	Limb-girdle muscular dystrophy, recessive (1)
-	-	1	Miyoshi muscular dystrophy 3 (1)
-	-	1	Miyoshi myopathy (1)
-	-	1	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.090
BayesDel_addAF	Benign	-0.65	T
BayesDel_noAF	Benign	-0.56
CADD	Benign	14
DANN	Uncertain	0.99
DEOGEN2	Benign	0.10	T
Eigen	Benign	-0.54
Eigen_PC	Benign	-0.45
FATHMM_MKL	Benign	0.084	N
LIST_S2	Benign	0.85	T
MetaRNN	Benign	0.00028	T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	1.3	L
PhyloP100		0.0010
PrimateAI	Benign	0.41	T
PROVEAN	Benign	-2.3	N
REVEL	Benign	0.054
Sift	Benign	0.14	T
Sift4G	Uncertain	0.059	T
Polyphen		0.011	B
Vest4		0.046
MutPred		0.17		Loss of catalytic residue at L322 (P = 0.1168)
MPC		0.10
ClinPred		0.0038	T
GERP RS		3.0
Varity_R		0.10
gMVP		0.70
Mutation Taster		=98/2	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs7481951; hg19: chr11-22271870; COSMIC: COSV61084696;