Genetic Variant ANO8:p.Ala1184Thr (chr19-17323666-C-T) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_020959.3(ANO8):c.3550G>A(p.Ala1184Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00023 ( 0 hom., cov: 0)

Exomes 𝑓: 0.000083 ( 0 hom. )

Consequence

ANO8
NM_020959.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -1.11

Publications

4 publications found

Variant links:

Genes affected

ANO8 (HGNC:29329): (anoctamin 8) Enables intracellular calcium activated chloride channel activity. Involved in chloride transport. Located in plasma membrane. [provided by Alliance of Genome Resources, Apr 2022]

ANO8 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.07105288).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_020959.3. 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
	ANO8	NM_020959.3	MANE Select	c.3550G>A	p.Ala1184Thr	missense	Exon 18 of 18	NP_066010.1	Q9HCE9-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ANO8	ENST00000159087.7	TSL:1 MANE Select	c.3550G>A	p.Ala1184Thr	missense	Exon 18 of 18	ENSP00000159087.4	Q9HCE9-1
ANO8	ENST00000597643.5	TSL:2	n.*2362G>A		non_coding_transcript_exon	Exon 18 of 18	ENSP00000469751.1	M0QYD2
ANO8	ENST00000597643.5	TSL:2	n.*2362G>A		3_prime_UTR	Exon 18 of 18	ENSP00000469751.1	M0QYD2

Frequencies

GnomAD3 genomes

AF:

0.000233

AC:

AN:

8572

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00197

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000251

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.0000830

AC:

AN:

36140

Hom.:

Cov.:

AF XY:

0.0000595

AC XY:

AN XY:

16810

show subpopulations

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

African (AFR)

AF:

0.00

AC:

AN:

776

American (AMR)

AF:

0.00

AC:

AN:

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

212

East Asian (EAS)

AF:

0.00

AC:

AN:

414

South Asian (SAS)

AF:

0.00

AC:

AN:

754

European-Finnish (FIN)

AF:

0.00

AC:

AN:

294

Middle Eastern (MID)

AF:

0.00

AC:

AN:

European-Non Finnish (NFE)

AF:

0.0000929

AC:

AN:

32292

Other (OTH)

AF:

0.00

AC:

AN:

1220

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.0160444), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.325

Heterozygous variant carriers

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

AF:

0.000233

AC:

AN:

8572

Hom.:

Cov.:

AF XY:

0.000455

AC XY:

AN XY:

4392

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

2220

American (AMR)

AF:

0.00

AC:

AN:

674

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

224

East Asian (EAS)

AF:

0.00197

AC:

AN:

508

South Asian (SAS)

AF:

0.00

AC:

AN:

406

European-Finnish (FIN)

AF:

0.00

AC:

AN:

364

Middle Eastern (MID)

AF:

0.00

AC:

AN:

European-Non Finnish (NFE)

AF:

0.000251

AC:

AN:

3984

Other (OTH)

AF:

0.00

AC:

AN:

108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

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:

0.00

Hom.:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.079

BayesDel_addAF

Benign

-0.27

BayesDel_noAF

Benign

-0.62

CADD

Benign

(source)

DANN

Benign

0.95

DEOGEN2

Benign

0.038

Eigen

Benign

-0.94

Eigen_PC

Benign

-0.94

FATHMM_MKL

Benign

0.063

LIST_S2

Benign

0.44

M_CAP

Pathogenic

0.61

MetaRNN

Benign

0.071

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.69

PhyloP100

-1.1

PrimateAI

Pathogenic

0.82

PROVEAN

Benign

-0.30

REVEL

Benign

0.037

Sift

Benign

0.087

Sift4G

Benign

0.087

Polyphen

0.037

Vest4

0.050

MutPred

0.21

Gain of glycosylation at A1184 (P = 1e-04)

MVP

0.15

ClinPred

0.11

GERP RS

2.3

Varity_R

0.034

gMVP

0.11

Mutation Taster

=95/5

polymorphism

(source)

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

Publications

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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

Computational scores

Splicing

Publications

Other links and lift over