11-22259652-C-T

Variant names:

• chr11-22259652-C-T
• rs397514736
• NM_213599.3:c.1541C>T

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM1 PM2 PP3_Moderate PP5

The NM_213599.3(ANO5):​c.1541C>T​(p.Thr514Ile) 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. Variant has been reported in ClinVar as Pathogenic (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T514R) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 31)
• Consequence: ANO5 NM_213599.3 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 7.89
• 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):

• 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.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 7 uncertain in NM_213599.3
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.884
• PP5: Variant 11-22259652-C-T is Pathogenic according to our data. Variant chr11-22259652-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 60689.Status of the report is no_assertion_criteria_provided, 0 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.1541C>T	p.Thr514Ile	missense	Exon 15 of 22	NP_998764.1	Q75V66
	ANO5	NM_001142649.2		c.1538C>T	p.Thr513Ile	missense	Exon 15 of 22	NP_001136121.1
	ANO5	NM_001410963.1		c.1499C>T	p.Thr500Ile	missense	Exon 14 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.1541C>T	p.Thr514Ile	missense	Exon 15 of 22	ENSP00000315371.9	Q75V66
	ANO5	ENST00000682341.1		c.1499C>T	p.Thr500Ile	missense	Exon 14 of 21	ENSP00000508251.1	A0A804HL91
	ANO5	ENST00000684663.1		c.1496C>T	p.Thr499Ile	missense	Exon 14 of 21	ENSP00000508009.1	A0A804HKP2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 31

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
1	-	-	Gnathodiaphyseal dysplasia (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.62
BayesDel_addAF	Pathogenic	0.35	D
BayesDel_noAF	Pathogenic	0.27
CADD	Pathogenic	26
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.32	T
Eigen	Pathogenic	0.77
Eigen_PC	Pathogenic	0.72
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.97	D
M_CAP	Uncertain	0.21	D
MetaRNN	Pathogenic	0.88	D
MetaSVM	Uncertain	-0.082	T
MutationAssessor	Uncertain	2.6	M
PhyloP100		7.9
PrimateAI	Uncertain	0.52	T
PROVEAN	Pathogenic	-5.5	D
REVEL	Pathogenic	0.71
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.0030	D
Polyphen		1.0	D
Vest4		0.89
MutPred		0.64		Gain of sheet (P = 0.0266)
MVP		0.80
MPC		0.48
ClinPred		1.0	D
GERP RS		5.5
Varity_R		0.80
gMVP		0.86
Mutation Taster		=5/95	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
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: rs397514736; hg19: chr11-22281198;