Genetic Variant ANO8:p.Arg1125His (chr19-17323842-C-T) – ACMG Classification: Likely_benign (-6 pts)

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_020959.3(ANO8):c.3374G>A(p.Arg1125His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000905 in 1,127,322 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000094 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000090 ( 0 hom. )

Consequence

ANO8
NM_020959.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.707

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 made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.084422946).

BS2

High AC in GnomAd4 at 14 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ANO8	NM_020959.3 link	c.3374G>A	p.Arg1125His	missense_variant	Exon 18 of 18	ENST00000159087.7	NP_066010.1	Q9HCE9-1
ANO8	XR_936199.4 link	n.4223G>A		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.3374G>A	p.Arg1125His	missense_variant	Exon 18 of 18	1	NM_020959.3	ENSP00000159087.4	Q9HCE9-1
ANO8	ENST00000597643.5 link	n.*2186G>A		non_coding_transcript_exon_variant	Exon 18 of 18	2		ENSP00000469751.1	M0QYD2
ANO8	ENST00000597643.5 link	n.*2186G>A		3_prime_UTR_variant	Exon 18 of 18	2		ENSP00000469751.1	M0QYD2

Frequencies

GnomAD3 genomes

AF:

0.0000939

AC:

AN:

149090

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000664

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000195

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.0000900

AC:

AN:

978232

Hom.:

Cov.:

AF XY:

0.0000782

AC XY:

AN XY:

460274

show subpopulations

Gnomad4 AFR exome

AF:

0.000105

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.000127

Gnomad4 NFE exome

AF:

0.0000971

Gnomad4 OTH exome

AF:

0.0000276

GnomAD4 genome

AF:

0.0000939

AC:

AN:

149090

Hom.:

Cov.:

AF XY:

0.0000826

AC XY:

AN XY:

72606

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.0000664

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000195

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.000113

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Mar 05, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.3374G>A (p.R1125H) 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 3374, causing the arginine (R) at amino acid position 1125 to be replaced by a histidine (H). 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

0.13

BayesDel_addAF

Benign

-0.17

BayesDel_noAF

Benign

-0.48

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.044

Eigen

Benign

-0.75

Eigen_PC

Benign

-0.68

FATHMM_MKL

Benign

0.088

LIST_S2

Benign

0.52

M_CAP

Pathogenic

0.46

MetaRNN

Benign

0.084

MetaSVM

Benign

-0.98

MutationAssessor

Benign

0.90

PrimateAI

Pathogenic

0.85

PROVEAN

Benign

-0.48

REVEL

Benign

0.035

Sift

Benign

0.33

Sift4G

Benign

0.20

Polyphen

0.0060

Vest4

0.068

MutPred

0.30

Loss of methylation at R1125 (P = 0.0129);

MVP

0.10

ClinPred

0.22

GERP RS

0.78

Varity_R

0.023

gMVP

0.13

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over