Genetic Variant ANO8:p.Gly1111Glu (chr19-17323884-C-T) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_020959.3(ANO8):c.3332G>A(p.Gly1111Glu) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000206 in 968,756 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/24 in silico tools predict 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 Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

ANO8
NM_020959.3 missense, splice_region

Scores

Splicing: ADA: 0.6854

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.0210

Publications

0 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:

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ACMG classification

Classification was made for transcript

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=0.2007088).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ANO8	NM_020959.3 link	c.3332G>A	p.Gly1111Glu	missense_variant, splice_region_variant	Exon 18 of 18	ENST00000159087.7	NP_066010.1	Q9HCE9-1
ANO8	XR_936199.4 link	n.4181G>A		splice_region_variant, non_coding_transcript_exon_variant	Exon 18 of 18

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
ANO8	ENST00000159087.7 link	c.3332G>A	p.Gly1111Glu	missense_variant, splice_region_variant	Exon 18 of 18	1	NM_020959.3	ENSP00000159087.4	Q9HCE9-1
ANO8	ENST00000597643.5 link	n.*2144G>A		splice_region_variant, non_coding_transcript_exon_variant	Exon 18 of 18	2		ENSP00000469751.1	M0QYD2
ANO8	ENST00000597643.5 link	n.*2144G>A		3_prime_UTR_variant	Exon 18 of 18	2		ENSP00000469751.1	M0QYD2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000206

AC:

AN:

968756

Hom.:

Cov.:

AF XY:

0.00000439

AC XY:

AN XY:

455394

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

18844

American (AMR)

AF:

0.00

AC:

AN:

4942

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

9394

East Asian (EAS)

AF:

0.00

AC:

AN:

15658

South Asian (SAS)

AF:

0.00

AC:

AN:

18508

European-Finnish (FIN)

AF:

0.00

AC:

AN:

15066

Middle Eastern (MID)

AF:

0.00

AC:

AN:

2300

European-Non Finnish (NFE)

AF:

0.00000118

AC:

AN:

848420

Other (OTH)

AF:

0.0000281

AC:

AN:

35624

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.700

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Dec 21, 2023

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.3332G>A (p.G1111E) alteration is located in exon 18 (coding exon 18) of the ANO8 gene. This alteration results from a G to A substitution at nucleotide position 3332, causing the glycine (G) at amino acid position 1111 to be replaced by a glutamic acid (E). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.25

BayesDel_addAF

Benign

-0.11

BayesDel_noAF

Benign

-0.40

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.040

Eigen

Benign

-0.071

Eigen_PC

Benign

-0.024

FATHMM_MKL

Benign

0.57

LIST_S2

Benign

0.54

M_CAP

Pathogenic

0.51

MetaRNN

Benign

0.20

MetaSVM

Benign

-0.93

MutationAssessor

Benign

0.90

PhyloP100

0.021

PrimateAI

Pathogenic

0.88

PROVEAN

Benign

-1.1

REVEL

Benign

0.11

Sift

Benign

0.11

Sift4G

Benign

0.39

Polyphen

0.90

Vest4

0.21

MutPred

0.22

Gain of solvent accessibility (P = 0.0456);

MVP

0.082

ClinPred

0.32

GERP RS

3.8

Varity_R

0.15

gMVP

0.10

Mutation Taster

=69/31

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.69

dbscSNV1_RF

Benign

0.46

SpliceAI score (max)

0.10

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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chr19-17323884-C-T

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over