rs886042339

Positions:

• chr11-22255393-G-C
• chr11-22255393-G-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_213599.3(ANO5):​c.1203G>C​(p.Trp401Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: ANO5 NM_213599.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 9.67

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.958

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ANO5	NM_213599.3	c.1203G>C	p.Trp401Cys	missense_variant	13/22	ENST00000324559.9	NP_998764.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ANO5	ENST00000324559.9	c.1203G>C	p.Trp401Cys	missense_variant	13/22	1	NM_213599.3	ENSP00000315371	P2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.57	D
BayesDel_noAF	Pathogenic	0.57
CADD	Pathogenic	32
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.64	D
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.94
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	1.0	D
M_CAP	Pathogenic	0.34	D
MetaRNN	Pathogenic	0.96	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.2	H
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.82	D
PROVEAN	Pathogenic	-12	D
REVEL	Pathogenic	0.94
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.91
MutPred		0.81		Loss of catalytic residue at W401 (P = 0.0629);
MVP		0.91
MPC		0.59
ClinPred		1.0	D
GERP RS		5.1
Varity_R		0.94
gMVP		0.99

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs886042339; hg19: chr11-22276939;