19-17323818-G-A

Position:

• chr19-17323818-G-A

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_020959.3(ANO8):​c.3398C>T​(p.Pro1133Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000506 in 987,570 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000051 (0 hom.)
• Consequence: ANO8 NM_020959.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.07

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 Likely_benign. Variant got -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.10626608).
• BS2: High AC in GnomAdExome4 at 50 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ANO8	NM_020959.3	c.3398C>T	p.Pro1133Leu	missense_variant	18/18	ENST00000159087.7	NP_066010.1
ANO8	XR_936199.4	n.4247C>T		non_coding_transcript_exon_variant	18/18

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ANO8	ENST00000159087.7	c.3398C>T	p.Pro1133Leu	missense_variant	18/18	1	NM_020959.3	ENSP00000159087.4
ANO8	ENST00000597643.5	n.*2210C>T		non_coding_transcript_exon_variant	18/18	2		ENSP00000469751.1
ANO8	ENST00000597643.5	n.*2210C>T		3_prime_UTR_variant	18/18	2		ENSP00000469751.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.0000506 AC: 50 AN: 987570 Hom.: 0 Cov.: 32 AF XY: 0.0000452 AC XY: 21 AN XY: 464794

Gnomad4 AFR exome AF: 0.00

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: 0.00

Gnomad4 NFE exome AF: 0.0000570

Gnomad4 OTH exome AF: 0.0000271

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000756

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

Oct 03, 2022

The c.3398C>T (p.P1133L) alteration is located in exon 18 (coding exon 18) of the ANO8 gene. This alteration results from a C to T substitution at nucleotide position 3398, causing the proline (P) at amino acid position 1133 to be replaced by a leucine (L). 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	0.081
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.44
CADD	Benign	15
DANN	Benign	0.97
DEOGEN2	Benign	0.038	T
Eigen	Benign	-0.85
Eigen_PC	Benign	-0.84
FATHMM_MKL	Benign	0.030	N
LIST_S2	Benign	0.49	T
M_CAP	Pathogenic	0.35	D
MetaRNN	Benign	0.11	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	0.55	N
PrimateAI	Uncertain	0.76	T
PROVEAN	Benign	-0.51	N
REVEL	Benign	0.12
Sift	Uncertain	0.021	D
Sift4G	Uncertain	0.0050	D
Polyphen		0.0	B
Vest4		0.23
MutPred		0.28		Loss of glycosylation at P1133 (P = 0.0019);
MVP		0.068
ClinPred		0.076	T
GERP RS		1.7
Varity_R		0.073
gMVP		0.17

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: rs2074254936; hg19: chr19-17434627;