rs137854525

Variant names:

• chr11-22257738-C-AT
• rs137854525
• NM_213599.3:c.1391delCinsAT

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PVS1 PM2

The NM_213599.3(ANO5):​c.1391delCinsAT​(p.Ala464AspfsTer30) variant causes a frameshift, missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as not provided (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A464D) has been classified as Likely pathogenic. Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: ANO5 NM_213599.3 frameshift, missense
• Clinical Significance: not provided no classification provided O:1
• Conservation: PhyloP100: 4.00
• 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):

• 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: Pathogenic. The variant received 10 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage

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.1391delCinsAT	p.Ala464AspfsTer30	frameshift missense	Exon 14 of 22	NP_998764.1	Q75V66
	ANO5	NM_001142649.2		c.1388delCinsAT	p.Ala463AspfsTer30	frameshift missense	Exon 14 of 22	NP_001136121.1
	ANO5	NM_001410963.1		c.1349delCinsAT	p.Ala450AspfsTer30	frameshift missense	Exon 13 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.1391delCinsAT	p.Ala464AspfsTer30	frameshift missense	Exon 14 of 22	ENSP00000315371.9	Q75V66
	ANO5	ENST00000682341.1		c.1349delCinsAT	p.Ala450AspfsTer30	frameshift missense	Exon 13 of 21	ENSP00000508251.1	A0A804HL91
	ANO5	ENST00000684663.1		c.1346delCinsAT	p.Ala449AspfsTer30	frameshift missense	Exon 13 of 21	ENSP00000508009.1	A0A804HKP2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: not provided

Revision: no classification provided

Pathogenic	VUS	Benign	Condition
-	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		4.0
Mutation Taster		=5/195	disease causing (fs/PTC)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs137854525; hg19: chr11-22279284;