Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_StrongBP6_Moderate

The ENST00000324559.9(ANO5):c.2236-6C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000465 in 1,389,038 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.00018 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00047 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

ANO5
ENST00000324559.9 splice_region, intron

Scores

Splicing: ADA: 0.00002067

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: -0.0640

Publications

1 publications found

Variant links:

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)

ANO5 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -6 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.79).

BP6

Variant 11-22274563-C-T is Benign according to our data. Variant chr11-22274563-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 468840.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000324559.9. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein
ANO5	NM_213599.3	MANE Select	c.2236-6C>T	splice_region intron	N/A	NP_998764.1
ANO5	NM_001142649.2		c.2233-6C>T	splice_region intron	N/A	NP_001136121.1
ANO5	NM_001410963.1		c.2194-6C>T	splice_region intron	N/A	NP_001397892.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein
ANO5	ENST00000324559.9	TSL:1 MANE Select	c.2236-6C>T	splice_region intron	N/A	ENSP00000315371.9
ANO5	ENST00000682341.1		c.2194-6C>T	splice_region intron	N/A	ENSP00000508251.1
ANO5	ENST00000684663.1		c.2191-6C>T	splice_region intron	N/A	ENSP00000508009.1

Frequencies

GnomAD3 genomes

AF:

0.000177

AC:

AN:

147160

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000100

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00138

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000135

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00230

AC:

483

AN:

209968

AF XY:

0.00166

show subpopulations

Gnomad AFR exome

AF:

0.00416

Gnomad AMR exome

AF:

0.00361

Gnomad ASJ exome

AF:

0.00332

Gnomad EAS exome

AF:

0.00257

Gnomad FIN exome

AF:

0.000931

Gnomad NFE exome

AF:

0.00208

Gnomad OTH exome

AF:

0.00228

GnomAD4 exome

AF:

0.000465

AC:

646

AN:

1389038

Hom.:

Cov.:

AF XY:

0.000432

AC XY:

296

AN XY:

685154

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00242

AC:

AN:

30634

American (AMR)

AF:

0.00550

AC:

191

AN:

34750

Ashkenazi Jewish (ASJ)

AF:

0.00119

AC:

AN:

23544

East Asian (EAS)

AF:

0.000395

AC:

AN:

37990

South Asian (SAS)

AF:

0.000444

AC:

AN:

74392

European-Finnish (FIN)

AF:

0.000520

AC:

AN:

48104

Middle Eastern (MID)

AF:

0.000925

AC:

AN:

5404

European-Non Finnish (NFE)

AF:

0.000219

AC:

236

AN:

1077144

Other (OTH)

AF:

0.000683

AC:

AN:

57076

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.262

Heterozygous variant carriers

127

190

254

317

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.000177

AC:

AN:

147160

Hom.:

Cov.:

AF XY:

0.000210

AC XY:

AN XY:

71454

show subpopulations

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.000100

AC:

AN:

40012

American (AMR)

AF:

0.00

AC:

AN:

14850

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3422

East Asian (EAS)

AF:

0.00

AC:

AN:

5026

South Asian (SAS)

AF:

0.00

AC:

AN:

4668

European-Finnish (FIN)

AF:

0.00138

AC:

AN:

9394

Middle Eastern (MID)

AF:

0.00

AC:

AN:

314

European-Non Finnish (NFE)

AF:

0.000135

AC:

AN:

66530

Other (OTH)

AF:

0.00

AC:

AN:

2044

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.250

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0238

Hom.:

ClinVar

ClinVar submissions as Germline

Significance:Likely benign

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

Gnathodiaphyseal dysplasia;C1969785:Autosomal recessive limb-girdle muscular dystrophy type 2L (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.79

CADD

Benign

2.2

(source)

DANN

Benign

0.45

PhyloP100

-0.064

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000021

dbscSNV1_RF

Benign

0.010

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

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over