chr19-17323675-G-C

Position:

• chr19-17323675-G-C

Variant summary

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

The NM_020959.3(ANO8):​c.3541C>G​(p.Pro1181Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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: 28)
  • Exomes 𝑓: 0.0000080 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: ANO8 NM_020959.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.252

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=0.11220816).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ANO8	NM_020959.3	c.3541C>G	p.Pro1181Ala	missense_variant	18/18	ENST00000159087.7	NP_066010.1
ANO8	XR_936199.4	n.4390C>G		non_coding_transcript_exon_variant	18/18

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ANO8	ENST00000159087.7	c.3541C>G	p.Pro1181Ala	missense_variant	18/18	1	NM_020959.3	ENSP00000159087.4
ANO8	ENST00000597643.5	n.*2353C>G		non_coding_transcript_exon_variant	18/18	2		ENSP00000469751.1
ANO8	ENST00000597643.5	n.*2353C>G		3_prime_UTR_variant	18/18	2		ENSP00000469751.1

Frequencies

GnomAD3 genomes Cov.: 28

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000796 AC: 5 AN: 628136 Hom.: 0 Cov.: 25 AF XY: 0.00000686 AC XY: 2 AN XY: 291560

Gnomad4 AFR exome AF: 0.0000839

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: 0.00502

Gnomad4 NFE exome AF: 0.00000175

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 28

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

Mar 03, 2022

The c.3541C>G (p.P1181A) alteration is located in exon 18 (coding exon 18) of the ANO8 gene. This alteration results from a C to G substitution at nucleotide position 3541, causing the proline (P) at amino acid position 1181 to be replaced by an alanine (A). 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	0.059
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.50
CADD	Benign	8.3
DANN	Benign	0.69
DEOGEN2	Benign	0.041	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.070	N
LIST_S2	Benign	0.41	T
M_CAP	Pathogenic	0.57	D
MetaRNN	Benign	0.11	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.90	L
PrimateAI	Pathogenic	0.80	T
PROVEAN	Benign	-0.31	N
REVEL	Benign	0.0050
Sift	Benign	0.23	T
Sift4G	Benign	0.070	T
Polyphen		0.049	B
Vest4		0.19
MutPred		0.32		Loss of glycosylation at P1181 (P = 0.0156);
MVP		0.22
ClinPred		0.036	T
GERP RS		0.56
Varity_R		0.027
gMVP		0.11

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: rs1191782460; hg19: chr19-17434484; COSMIC: COSV105030391; COSMIC: COSV105030391;