19-17323744-C-T

Position:

• chr19-17323744-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_020959.3(ANO8):​c.3472G>A​(p.Gly1158Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000285 in 1,050,976 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: not found (cov: 30)
  • Exomes 𝑓: 0.0000029 (0 hom.)
• Consequence: ANO8 NM_020959.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.577

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 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.21161038).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ANO8	NM_020959.3	c.3472G>A	p.Gly1158Arg	missense_variant	18/18	ENST00000159087.7	NP_066010.1
ANO8	XR_936199.4	n.4321G>A		non_coding_transcript_exon_variant	18/18

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ANO8	ENST00000159087.7	c.3472G>A	p.Gly1158Arg	missense_variant	18/18	1	NM_020959.3	ENSP00000159087.4
ANO8	ENST00000597643.5	n.*2284G>A		non_coding_transcript_exon_variant	18/18	2		ENSP00000469751.1
ANO8	ENST00000597643.5	n.*2284G>A		3_prime_UTR_variant	18/18	2		ENSP00000469751.1

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome AF: 0.00000285 AC: 3 AN: 1050976 Hom.: 0 Cov.: 31 AF XY: 0.00000403 AC XY: 2 AN XY: 496064

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000122

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 30

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 18, 2023

The c.3472G>A (p.G1158R) 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 3472, causing the glycine (G) at amino acid position 1158 to be replaced by an arginine (R). 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	0.27
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.41
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.060	T
Eigen	Benign	-0.15
Eigen_PC	Benign	-0.24
FATHMM_MKL	Benign	0.12	N
LIST_S2	Benign	0.57	T
M_CAP	Pathogenic	0.79	D
MetaRNN	Benign	0.21	T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	0.90	L
PrimateAI	Pathogenic	0.91	D
PROVEAN	Benign	-1.4	N
REVEL	Benign	0.12
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.0070	D
Polyphen		0.99	D
Vest4		0.15
MutPred		0.27		Gain of MoRF binding (P = 0.0278);
MVP		0.043
ClinPred		0.64	D
GERP RS		2.3
Varity_R		0.17
gMVP		0.13

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

LitVar

Other links and lift over

dbSNP: rs2074254044; hg19: chr19-17434553;