NM_213599.3:c.87G>C

Variant names:

• chr11-22203850-G-C
• rs1554919178
• NM_213599.3:c.87G>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_213599.3(ANO5):​c.87G>C​(p.Glu29Asp) variant causes a missense, 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 benign outcome for this variant. 17/26 in silico tools predict a benign outcome for this variant. 2/3 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. E29E) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: ANO5 NM_213599.3 missense, splice_region
• Scores: Splicing: ADA: 0.6245
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.76
• 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.1080682).

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.87G>C	p.Glu29Asp	missense splice_region	Exon 2 of 22	NP_998764.1
	ANO5	NM_001142649.2		c.87G>C	p.Glu29Asp	missense splice_region	Exon 2 of 22	NP_001136121.1
	ANO5	NM_001410963.1		c.87G>C	p.Glu29Asp	missense splice_region	Exon 2 of 21	NP_001397892.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ANO5	ENST00000324559.9	TSL:1 MANE Select	c.87G>C	p.Glu29Asp	missense splice_region	Exon 2 of 22	ENSP00000315371.9
	ANO5	ENST00000682341.1		c.87G>C	p.Glu29Asp	missense splice_region	Exon 2 of 21	ENSP00000508251.1
	ANO5	ENST00000684663.1		c.87G>C	p.Glu29Asp	missense splice_region	Exon 2 of 21	ENSP00000508009.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 25

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.074
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.47
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.041	T
Eigen	Benign	-0.42
Eigen_PC	Benign	-0.25
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Benign	0.41	T
M_CAP	Benign	0.0061	T
MetaRNN	Benign	0.11	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	0.55	N
PhyloP100		1.8
PrimateAI	Benign	0.39	T
PROVEAN	Benign	-0.47	N
REVEL	Benign	0.060
Sift	Benign	0.17	T
Sift4G	Benign	0.56	T
Polyphen		0.0030	B
Vest4		0.18
MutPred		0.31		Loss of helix (P = 0.0237)
MVP		0.30
MPC		0.079
ClinPred		0.19	T
GERP RS		3.2
Varity_R		0.081
gMVP		0.20
Mutation Taster		=67/33	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.62
dbscSNV1_RF	Benign	0.56
SpliceAI score (max)		0.53		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.53		Position offset: 0

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

Other links and lift over

dbSNP: rs1554919178; hg19: chr11-22225396;