rs76850415

Variant names:

• chr11-22279531-A-G
• rs76850415
• NM_213599.3:c.2521-13A>G

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.2521-13A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0354 in 1,598,086 control chromosomes in the GnomAD database, including 1,120 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.026 (69 hom., cov: 32)
  • Exomes 𝑓: 0.036 (1051 hom.)
• Consequence: ANO5 NM_213599.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: -1.57
• Publications: 1 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 11-22279531-A-G is Benign according to our data. Variant chr11-22279531-A-G is described in ClinVar as Benign. ClinVar VariationId is 96680.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 = 0.0263 (3990/151922) while in subpopulation NFE AF = 0.0405 (2743/67790). AF 95% confidence interval is 0.0392. There are 69 homozygotes in GnomAd4. There are 1861 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 69 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ANO5	NM_213599.3	MANE Select	c.2521-13A>G		intron	N/A	NP_998764.1
	ANO5	NM_001142649.2		c.2518-13A>G		intron	N/A	NP_001136121.1
	ANO5	NM_001410963.1		c.2479-13A>G		intron	N/A	NP_001397892.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ANO5	ENST00000324559.9	TSL:1 MANE Select	c.2521-13A>G		intron	N/A	ENSP00000315371.9
	ANO5	ENST00000682341.1		c.2479-13A>G		intron	N/A	ENSP00000508251.1
	ANO5	ENST00000684663.1		c.2476-13A>G		intron	N/A	ENSP00000508009.1

Frequencies

GnomAD3 genomes AF: 0.0263 AC: 3991 AN: 151804 Hom.: 69 Cov.: 32

Gnomad AFR AF: 0.00795

Gnomad AMI AF: 0.0461

Gnomad AMR AF: 0.0204

Gnomad ASJ AF: 0.0450

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.0209

Gnomad FIN AF: 0.0203

Gnomad MID AF: 0.0222

Gnomad NFE AF: 0.0405

Gnomad OTH AF: 0.0414

GnomAD2 exomes AF: 0.0292 AC: 7270 AN: 248662 AF XY: 0.0303

Gnomad AFR exome AF: 0.00650

Gnomad AMR exome AF: 0.0165

Gnomad ASJ exome AF: 0.0439

Gnomad EAS exome AF: 0.0000545

Gnomad FIN exome AF: 0.0221

Gnomad NFE exome AF: 0.0427

Gnomad OTH exome AF: 0.0339

GnomAD4 exome AF: 0.0364 AC: 52638 AN: 1446164 Hom.: 1051 Cov.: 31 AF XY: 0.0365 AC XY: 26274 AN XY: 720238

African (AFR) AF: 0.00614 AC: 203 AN: 33088

American (AMR) AF: 0.0171 AC: 760 AN: 44524

Ashkenazi Jewish (ASJ) AF: 0.0467 AC: 1213 AN: 25998

East Asian (EAS) AF: 0.000126 AC: 5 AN: 39592

South Asian (SAS) AF: 0.0234 AC: 2008 AN: 85866

European-Finnish (FIN) AF: 0.0233 AC: 1240 AN: 53312

Middle Eastern (MID) AF: 0.0427 AC: 208 AN: 4874

European-Non Finnish (NFE) AF: 0.0410 AC: 45025 AN: 1099074

Other (OTH) AF: 0.0330 AC: 1976 AN: 59836

GnomAD4 genome AF: 0.0263 AC: 3990 AN: 151922 Hom.: 69 Cov.: 32 AF XY: 0.0251 AC XY: 1861 AN XY: 74278

African (AFR) AF: 0.00792 AC: 329 AN: 41520

American (AMR) AF: 0.0204 AC: 311 AN: 15236

Ashkenazi Jewish (ASJ) AF: 0.0450 AC: 156 AN: 3466

East Asian (EAS) AF: 0.000386 AC: 2 AN: 5180

South Asian (SAS) AF: 0.0209 AC: 101 AN: 4830

European-Finnish (FIN) AF: 0.0203 AC: 215 AN: 10596

Middle Eastern (MID) AF: 0.0204 AC: 6 AN: 294

European-Non Finnish (NFE) AF: 0.0405 AC: 2743 AN: 67790

Other (OTH) AF: 0.0405 AC: 85 AN: 2098

Alfa AF: 0.0359 Hom.: 189

Bravo AF: 0.0260

Asia WGS AF: 0.00924 AC: 32 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	-	2	not provided (2)
-	-	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
BayesDel_noAF	Benign	-0.83
CADD	Benign	2.3
DANN	Benign	0.55
PhyloP100		-1.6
Mutation Taster		=100/0	polymorphism (auto)

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: rs76850415; hg19: chr11-22301077;