rs773736505

Variant names:

• chr11-22236161-A-G
• rs773736505
• NM_213599.3:c.649-2A>G

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PVS1_Moderate PP5_Very_Strong

The NM_213599.3(ANO5):​c.649-2A>G variant causes a splice acceptor, intron change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000486 in 1,439,340 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000049 (0 hom.)
• Consequence: ANO5 NM_213599.3 splice_acceptor, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 8.12
• Publications: 2 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: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.04157549 fraction of the gene. Cryptic splice site detected, with MaxEntScore 4.8, offset of 20, new splice context is: gtgtactatattctctcaAGatg. Cryptic site results in frameshift change. If cryptic site found is not functional and variant results in exon loss, it results in inframe change.
• PP5: Variant 11-22236161-A-G is Pathogenic according to our data. Variant chr11-22236161-A-G is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 548990.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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.649-2A>G		splice_acceptor intron	N/A	NP_998764.1	Q75V66
	ANO5	NM_001142649.2		c.646-2A>G		splice_acceptor intron	N/A	NP_001136121.1
	ANO5	NM_001410963.1		c.607-2A>G		splice_acceptor intron	N/A	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.649-2A>G		splice_acceptor intron	N/A	ENSP00000315371.9	Q75V66
	ANO5	ENST00000682341.1		c.607-2A>G		splice_acceptor intron	N/A	ENSP00000508251.1	A0A804HL91
	ANO5	ENST00000684663.1		c.604-2A>G		splice_acceptor intron	N/A	ENSP00000508009.1	A0A804HKP2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000486 AC: 7 AN: 1439340 Hom.: 0 Cov.: 28 AF XY: 0.00000279 AC XY: 2 AN XY: 717750

African (AFR) AF: 0.00 AC: 0 AN: 32974

American (AMR) AF: 0.00 AC: 0 AN: 44620

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25954

East Asian (EAS) AF: 0.00 AC: 0 AN: 39414

South Asian (SAS) AF: 0.00 AC: 0 AN: 85770

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53334

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5708

European-Non Finnish (NFE) AF: 0.00000641 AC: 7 AN: 1091908

Other (OTH) AF: 0.00 AC: 0 AN: 59658

GnomAD4 genome Cov.: 32

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ClinVar

ClinVar submissions

Significance: Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
1	-	-	Autosomal recessive limb-girdle muscular dystrophy type 2L (1)
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
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.32
CADD	Pathogenic	30
DANN	Uncertain	1.0
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.98
FATHMM_MKL	Pathogenic	1.0	D
PhyloP100		8.1
GERP RS		5.8
Mutation Taster		=0/100	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.93
SpliceAI score (max)		0.65		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.65		Position offset: 2

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

Other links and lift over

dbSNP: rs773736505; hg19: chr11-22257707;