chr11-22193476-T-TTAACGAGCTGGCGAAGA

Variant names:

• chr11-22193476-T-TTAACGAGCTGGCGAAGA
• rs775383795
• NM_213599.3:c.-15_2dupAACGAGCTGGCGAAGAT

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 8P and 1B. PVS1 BP6

The NM_213599.3(ANO5):​c.-15_2dupAACGAGCTGGCGAAGAT​(p.Met1fs) variant causes a frameshift, start lost change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000323 in 1,611,066 control chromosomes in the GnomAD database, including 1 homozygotes. It is difficult to determine the true allele frequency of this variant because it is of type INS_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000034 (1 hom.)
• Consequence: ANO5 NM_213599.3 frameshift, start_lost
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: -0.845
• 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):

• 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: Likely_pathogenic. The variant received 7 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 161 pathogenic variants in the truncated region.
• BP6: Variant 11-22193476-T-TTAACGAGCTGGCGAAGA is Benign according to our data. Variant chr11-22193476-T-TTAACGAGCTGGCGAAGA is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 502204.

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.-15_2dupAACGAGCTGGCGAAGAT	p.Met1fs	frameshift start_lost	Exon 1 of 22	NP_998764.1	Q75V66
	ANO5	NM_001142649.2		c.-15_2dupAACGAGCTGGCGAAGAT	p.Met1fs	frameshift start_lost	Exon 1 of 22	NP_001136121.1
	ANO5	NM_001410963.1		c.-15_2dupAACGAGCTGGCGAAGAT	p.Met1fs	frameshift start_lost	Exon 1 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.-15_2dupAACGAGCTGGCGAAGAT	p.Met1fs	frameshift start_lost	Exon 1 of 22	ENSP00000315371.9	Q75V66
	ANO5	ENST00000682341.1		c.-15_2dupAACGAGCTGGCGAAGAT	p.Met1fs	frameshift start_lost	Exon 1 of 21	ENSP00000508251.1	A0A804HL91
	ANO5	ENST00000684663.1		c.-15_2dupAACGAGCTGGCGAAGAT	p.Met1fs	frameshift start_lost	Exon 1 of 21	ENSP00000508009.1	A0A804HKP2

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152128 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000582

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000746 AC: 18 AN: 241320 AF XY: 0.0000765

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000992

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000336 AC: 49 AN: 1458820 Hom.: 1 Cov.: 34 AF XY: 0.0000358 AC XY: 26 AN XY: 725300

African (AFR) AF: 0.00 AC: 0 AN: 33450

American (AMR) AF: 0.00 AC: 0 AN: 44406

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26056

East Asian (EAS) AF: 0.00119 AC: 47 AN: 39624

South Asian (SAS) AF: 0.00 AC: 0 AN: 85310

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52846

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111060

Other (OTH) AF: 0.0000332 AC: 2 AN: 60304

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152246 Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1 AN XY: 74430

African (AFR) AF: 0.00 AC: 0 AN: 41574

American (AMR) AF: 0.00 AC: 0 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.000583 AC: 3 AN: 5146

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10612

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68000

Other (OTH) AF: 0.00 AC: 0 AN: 2114

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	1	Gnathodiaphyseal dysplasia;C1969785:Autosomal recessive limb-girdle muscular dystrophy type 2L (1)
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.84

Splicing

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

Other links and lift over

dbSNP: rs775383795; hg19: chr11-22215022;