rs61910685

Variant names:

• chr11-22274720-C-T
• rs61910685
• NM_213599.3:c.2387C>T

Your query was ambiguous. Multiple possible variants found:

• chr11-22274720-C-T
• chr11-22274720-C-G

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 2P and 20B. PM1 BP4_Strong BP6_Very_Strong BS1 BS2

The NM_213599.3(ANO5):​c.2387C>T​(p.Ser796Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0104 in 1,613,342 control chromosomes in the GnomAD database, including 131 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 (★★). Synonymous variant affecting the same amino acid position (i.e. S796S) has been classified as Likely benign. The gene ANO5 is included in the ClinGen Criteria Specification Registry.

• Frequency:
  • Genomes: 𝑓 0.0080 (14 hom., cov: 32)
  • Exomes 𝑓: 0.011 (117 hom.)
• Consequence: ANO5 NM_213599.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:17
• Conservation: PhyloP100: 0.115
• Publications: 20 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 -18 ACMG points.

• PM1: In a topological_domain Extracellular (size 80) in uniprot entity ANO5_HUMAN there are 6 pathogenic changes around while only 2 benign (75%) in NM_213599.3
• BP4: Computational evidence support a benign effect (MetaRNN=0.006762922).
• BP6: Variant 11-22274720-C-T is Benign according to our data. Variant chr11-22274720-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 195543.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00803 (1221/152026) while in subpopulation NFE AF = 0.0126 (856/67874). AF 95% confidence interval is 0.0119. There are 14 homozygotes in GnomAd4. There are 556 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 14 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.2387C>T	p.Ser796Leu	missense	Exon 20 of 22	NP_998764.1	Q75V66
	ANO5	NM_001142649.2		c.2384C>T	p.Ser795Leu	missense	Exon 20 of 22	NP_001136121.1
	ANO5	NM_001410963.1		c.2345C>T	p.Ser782Leu	missense	Exon 19 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.2387C>T	p.Ser796Leu	missense	Exon 20 of 22	ENSP00000315371.9	Q75V66
	ANO5	ENST00000682341.1		c.2345C>T	p.Ser782Leu	missense	Exon 19 of 21	ENSP00000508251.1	A0A804HL91
	ANO5	ENST00000684663.1		c.2342C>T	p.Ser781Leu	missense	Exon 19 of 21	ENSP00000508009.1	A0A804HKP2

Frequencies

GnomAD3 genomes AF: 0.00804 AC: 1221 AN: 151908 Hom.: 14 Cov.: 32

Gnomad AFR AF: 0.00186

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.00459

Gnomad ASJ AF: 0.0405

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00644

Gnomad FIN AF: 0.00236

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0126

Gnomad OTH AF: 0.0100

GnomAD2 exomes AF: 0.00868 AC: 2181 AN: 251252 AF XY: 0.00913

Gnomad AFR exome AF: 0.00179

Gnomad AMR exome AF: 0.00364

Gnomad ASJ exome AF: 0.0386

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00269

Gnomad NFE exome AF: 0.0118

Gnomad OTH exome AF: 0.00978

GnomAD4 exome AF: 0.0106 AC: 15487 AN: 1461316 Hom.: 117 Cov.: 34 AF XY: 0.0105 AC XY: 7628 AN XY: 726954

African (AFR) AF: 0.00134 AC: 45 AN: 33470

American (AMR) AF: 0.00427 AC: 191 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.0388 AC: 1014 AN: 26124

East Asian (EAS) AF: 0.00 AC: 0 AN: 39668

South Asian (SAS) AF: 0.00610 AC: 526 AN: 86244

European-Finnish (FIN) AF: 0.00281 AC: 150 AN: 53304

Middle Eastern (MID) AF: 0.00555 AC: 32 AN: 5766

European-Non Finnish (NFE) AF: 0.0116 AC: 12902 AN: 1111648

Other (OTH) AF: 0.0104 AC: 627 AN: 60372

GnomAD4 genome AF: 0.00803 AC: 1221 AN: 152026 Hom.: 14 Cov.: 32 AF XY: 0.00748 AC XY: 556 AN XY: 74328

African (AFR) AF: 0.00185 AC: 77 AN: 41528

American (AMR) AF: 0.00459 AC: 70 AN: 15258

Ashkenazi Jewish (ASJ) AF: 0.0405 AC: 140 AN: 3460

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.00644 AC: 31 AN: 4810

European-Finnish (FIN) AF: 0.00236 AC: 25 AN: 10602

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

European-Non Finnish (NFE) AF: 0.0126 AC: 856 AN: 67874

Other (OTH) AF: 0.00994 AC: 21 AN: 2112

Alfa AF: 0.00883 Hom.: 37

Bravo AF: 0.00773

TwinsUK AF: 0.0108 AC: 40

ALSPAC AF: 0.0101 AC: 39

ESP6500AA AF: 0.00295 AC: 13

ESP6500EA AF: 0.0124 AC: 107

ExAC AF: 0.00858 AC: 1042

Asia WGS AF: 0.00346 AC: 12 AN: 3478

EpiCase AF: 0.0138

EpiControl AF: 0.0139

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	6	not specified (6)
-	-	3	not provided (3)
-	-	2	Gnathodiaphyseal dysplasia (2)
-	-	1	ANO5-related disorder (1)
-	-	1	ANO5-Related Muscle Diseases (1)
-	-	1	Autosomal recessive limb-girdle muscular dystrophy type 2L (1)
-	-	1	Gnathodiaphyseal dysplasia;C1969785:Autosomal recessive limb-girdle muscular dystrophy type 2L (1)
-	-	1	Gnathodiaphyseal dysplasia;C1969785:Autosomal recessive limb-girdle muscular dystrophy type 2L;C2750076:Miyoshi muscular dystrophy 3 (1)
-	-	1	Miyoshi muscular dystrophy 3 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.067
BayesDel_addAF	Benign	-0.60	T
BayesDel_noAF	Benign	-0.62
CADD	Benign	8.3
DANN	Benign	0.91
DEOGEN2	Benign	0.057	T
Eigen	Benign	-1.0
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.057	N
LIST_S2	Benign	0.48	T
MetaRNN	Benign	0.0068	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.62	N
PhyloP100		0.12
PrimateAI	Benign	0.23	T
PROVEAN	Benign	-1.5	N
REVEL	Benign	0.043
Sift	Benign	0.21	T
Sift4G	Benign	0.52	T
Polyphen		0.0020	B
Vest4		0.12
MVP		0.28
MPC		0.076
ClinPred		0.0013	T
GERP RS		-0.96
Varity_R		0.039
gMVP		0.47
Mutation Taster		=96/4	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: rs61910685; hg19: chr11-22296266;