NM_213599.3:c.88C>T

Variant names:

• chr11-22211264-C-T
• rs747575706
• NM_213599.3:c.88C>T

Variant summary

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

The NM_213599.3(ANO5):​c.88C>T​(p.Gln30*) variant causes a stop gained, splice region change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. Q30Q) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: ANO5 NM_213599.3 stop_gained, splice_region
• Scores: Splicing: ADA: 0.1274
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.00
• 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):

• 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: Pathogenic. The variant received 10 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 158 pathogenic variants in the truncated region.
• 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ANO5	NM_213599.3	MANE Select	c.88C>T	p.Gln30*	stop_gained splice_region	Exon 3 of 22	NP_998764.1
	ANO5	NM_001410963.1		c.88C>T	p.Gln30*	stop_gained splice_region	Exon 3 of 21	NP_001397892.1
	ANO5	NM_001441294.1		c.10C>T	p.Gln4*	stop_gained splice_region	Exon 3 of 22	NP_001428223.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ANO5	ENST00000324559.9	TSL:1 MANE Select	c.88C>T	p.Gln30*	stop_gained splice_region	Exon 3 of 22	ENSP00000315371.9
	ANO5	ENST00000682341.1		c.88C>T	p.Gln30*	stop_gained splice_region	Exon 3 of 21	ENSP00000508251.1
	ANO5	ENST00000683197.1		c.88C>T	p.Gln30*	stop_gained splice_region	Exon 3 of 20	ENSP00000507641.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.42
CADD	Pathogenic	36
DANN	Uncertain	1.0
Eigen	Uncertain	0.50
Eigen_PC	Benign	0.20
FATHMM_MKL	Benign	0.65	D
PhyloP100		2.0
Vest4		0.80
GERP RS		3.0
Mutation Taster		=19/181	disease causing (fs/PTC)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.13
dbscSNV1_RF	Benign	0.32
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: rs747575706; hg19: chr11-22232810;