11-22255323-T-A

Variant names:

• chr11-22255323-T-A
• rs150412089
• NM_213599.3:c.1181-48T>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.1181-48T>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0115 in 1,456,584 control chromosomes in the GnomAD database, including 130 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0075 (9 hom., cov: 32)
  • Exomes 𝑓: 0.012 (121 hom.)
• Consequence: ANO5 NM_213599.3 intron
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.580
• Publications: 0 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=-0.8).
• BP6: Variant 11-22255323-T-A is Benign according to our data. Variant chr11-22255323-T-A is described in ClinVar as Likely_benign. ClinVar VariationId is 263310.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 = 0.00751 (1143/152120) while in subpopulation NFE AF = 0.0121 (824/67986). AF 95% confidence interval is 0.0114. There are 9 homozygotes in GnomAd4. There are 504 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 9 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.1181-48T>A		intron	N/A	NP_998764.1
	ANO5	NM_001142649.2		c.1178-48T>A		intron	N/A	NP_001136121.1
	ANO5	NM_001410963.1		c.1139-48T>A		intron	N/A	NP_001397892.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ANO5	ENST00000324559.9	TSL:1 MANE Select	c.1181-48T>A		intron	N/A	ENSP00000315371.9
	ANO5	ENST00000682341.1		c.1139-48T>A		intron	N/A	ENSP00000508251.1
	ANO5	ENST00000684663.1		c.1136-48T>A		intron	N/A	ENSP00000508009.1

Frequencies

GnomAD3 genomes AF: 0.00752 AC: 1143 AN: 152002 Hom.: 9 Cov.: 32

Gnomad AFR AF: 0.00288

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00754

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00249

Gnomad FIN AF: 0.00445

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.0121

Gnomad OTH AF: 0.00814

GnomAD2 exomes AF: 0.00747 AC: 1184 AN: 158520 AF XY: 0.00747

Gnomad AFR exome AF: 0.00235

Gnomad AMR exome AF: 0.00570

Gnomad ASJ exome AF: 0.00125

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00497

Gnomad NFE exome AF: 0.0125

Gnomad OTH exome AF: 0.00883

GnomAD4 exome AF: 0.0119 AC: 15566 AN: 1304464 Hom.: 121 Cov.: 24 AF XY: 0.0116 AC XY: 7535 AN XY: 648860

African (AFR) AF: 0.00220 AC: 61 AN: 27782

American (AMR) AF: 0.00573 AC: 182 AN: 31754

Ashkenazi Jewish (ASJ) AF: 0.00163 AC: 38 AN: 23326

East Asian (EAS) AF: 0.00 AC: 0 AN: 34408

South Asian (SAS) AF: 0.00184 AC: 127 AN: 68856

European-Finnish (FIN) AF: 0.00644 AC: 277 AN: 43018

Middle Eastern (MID) AF: 0.00427 AC: 17 AN: 3978

European-Non Finnish (NFE) AF: 0.0141 AC: 14362 AN: 1017360

Other (OTH) AF: 0.00930 AC: 502 AN: 53982

GnomAD4 genome AF: 0.00751 AC: 1143 AN: 152120 Hom.: 9 Cov.: 32 AF XY: 0.00678 AC XY: 504 AN XY: 74390

African (AFR) AF: 0.00287 AC: 119 AN: 41510

American (AMR) AF: 0.00753 AC: 115 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.00144 AC: 5 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00249 AC: 12 AN: 4820

European-Finnish (FIN) AF: 0.00445 AC: 47 AN: 10570

Middle Eastern (MID) AF: 0.0136 AC: 4 AN: 294

European-Non Finnish (NFE) AF: 0.0121 AC: 824 AN: 67986

Other (OTH) AF: 0.00806 AC: 17 AN: 2110

Alfa AF: 0.00800 Hom.: 2

Bravo AF: 0.00753

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not provided Benign:1

Aug 25, 2019

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	1.5
DANN	Benign	0.37
PhyloP100		0.58
Mutation Taster		=100/0	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: rs150412089; hg19: chr11-22276869;