11-418421-C-G

Variant names:

• chr11-418421-C-G
• rs146286449
• NM_001012302.3:c.2299G>C

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001012302.3(ANO9):​c.2299G>C​(p.Ala767Pro) 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. 16/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A767T) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: ANO9 NM_001012302.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.55
• Publications: 0 publications found

Genes affected

ANO9 (HGNC:20679): (anoctamin 9) The protein encoded by this gene is a member of the TMEM16 (anoctamin) family of proteins, some of which form integral membrane calcium-activated chloride channels. The function of the encoded protein has yet to be elucidated, although it may have channel-forming abilities and also may have phospholipid scramblase activity. This gene has been observed to be upregulated in stage II and III colorectal cancers. [provided by RefSeq, Dec 2016]

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.03982842).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001012302.3. 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
	ANO9	NM_001012302.3	MANE Select	c.2299G>C	p.Ala767Pro	missense	Exon 23 of 23	NP_001012302.2	A1A5B4-1
	ANO9	NM_001347882.2		c.1867G>C	p.Ala623Pro	missense	Exon 22 of 22	NP_001334811.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ANO9	ENST00000332826.7	TSL:1 MANE Select	c.2299G>C	p.Ala767Pro	missense	Exon 23 of 23	ENSP00000332788.6	A1A5B4-1
	ANO9	ENST00000528927.5	TSL:1	n.2410G>C		non_coding_transcript_exon	Exon 22 of 22
	ANO9	ENST00000884108.1		c.2440G>C	p.Ala814Pro	missense	Exon 22 of 22	ENSP00000554167.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.065
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.61
CADD	Benign	0.030
DANN	Benign	0.80
DEOGEN2	Benign	0.036	T
Eigen	Benign	-1.9
Eigen_PC	Benign	-1.9
FATHMM_MKL	Benign	0.029	N
LIST_S2	Benign	0.35	T
M_CAP	Uncertain	0.18	D
MetaRNN	Benign	0.040	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.0	N
PhyloP100		-1.5
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-0.82	N
REVEL	Benign	0.053
Sift	Uncertain	0.027	D
Sift4G	Benign	0.069	T
Polyphen		0.0010	B
Vest4		0.091
MutPred		0.13		Gain of glycosylation at A767 (P = 0.004)
MVP		0.030
MPC		0.31
ClinPred		0.073	T
GERP RS		-5.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.046
gMVP		0.21
Mutation Taster		=99/1	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs146286449; hg19: chr11-418421;