NM_020959.3:c.3541C>G

Variant names:

• chr19-17323675-G-C
• rs1191782460
• NM_020959.3:c.3541C>G

Variant summary

Our verdict is Uncertain significance. The variant received 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. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P1181T) has been classified 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
• Publications: 0 publications found

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]

ACMG classification

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=0.11220816).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_020959.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ANO8	NM_020959.3	MANE Select	c.3541C>G	p.Pro1181Ala	missense	Exon 18 of 18	NP_066010.1	Q9HCE9-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ANO8	ENST00000159087.7	TSL:1 MANE Select	c.3541C>G	p.Pro1181Ala	missense	Exon 18 of 18	ENSP00000159087.4	Q9HCE9-1
	ANO8	ENST00000597643.5	TSL:2	n.*2353C>G		non_coding_transcript_exon	Exon 18 of 18	ENSP00000469751.1	M0QYD2
	ANO8	ENST00000597643.5	TSL:2	n.*2353C>G		3_prime_UTR	Exon 18 of 18	ENSP00000469751.1	M0QYD2

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

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0000839 AC: 1 AN: 11924

American (AMR) AF: 0.00 AC: 0 AN: 960

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3914

East Asian (EAS) AF: 0.00 AC: 0 AN: 3172

South Asian (SAS) AF: 0.00 AC: 0 AN: 12758

European-Finnish (FIN) AF: 0.00502 AC: 3 AN: 598

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1222

European-Non Finnish (NFE) AF: 0.00000175 AC: 1 AN: 572728

Other (OTH) AF: 0.00 AC: 0 AN: 20860

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.0000199620), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 28

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

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
PhyloP100		-0.25
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
Mutation Taster		=89/11	polymorphism

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

Other links and lift over

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