rs1489662261

Variant names:

• chr12-100922312-C-G
• rs1489662261
• NM_001286615.2:c.142C>G

Your query was ambiguous. Multiple possible variants found:

• chr12-100922312-C-G
• chr12-100922312-C-T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 3P and 2B. PM2 PP2 BP4_Moderate

The NM_001286615.2(ANO4):​c.142C>G​(p.Leu48Val) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 12/20 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. L48F) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: ANO4 NM_001286615.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.68
• Publications: 0 publications found

Genes affected

ANO4 (HGNC:23837): (anoctamin 4) Enables intracellular calcium activated chloride channel activity. Involved in chloride transport. Located in plasma membrane. [provided by Alliance of Genome Resources, Apr 2022]

ANO4 Gene-Disease associations (from GenCC):

• complex neurodevelopmental disorder

  Inheritance: AD Classification: MODERATE Submitted by: Ambry Genetics

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 7 curated pathogenic missense variants (we use a threshold of 10). The gene has 1 curated benign missense variants. Gene score misZ: 2.5332 (below the threshold of 3.09). Trascript score misZ: 3.1552 (above the threshold of 3.09). GenCC associations: The gene is linked to complex neurodevelopmental disorder.
• BP4: Computational evidence support a benign effect (MetaRNN=0.2587163).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ANO4	NM_001286615.2	c.142C>G	p.Leu48Val	missense_variant	Exon 3 of 28	ENST00000392977.8	NP_001273544.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ANO4	ENST00000392977.8	c.142C>G	p.Leu48Val	missense_variant	Exon 3 of 28	2	NM_001286615.2	ENSP00000376703.3
ANO4	ENST00000644049.1	c.640C>G	p.Leu214Val	missense_variant	Exon 5 of 30			ENSP00000494481.1
ANO4	ENST00000549155.6	n.640C>G		non_coding_transcript_exon_variant	Exon 5 of 11	2		ENSP00000449116.2
ANO4	ENST00000392979.7	c.56-17003C>G		intron_variant	Intron 2 of 26	2		ENSP00000376705.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.095
BayesDel_addAF	Benign	-0.0027	T
BayesDel_noAF	Benign	-0.24
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.038	.;T
Eigen	Uncertain	0.37
Eigen_PC	Uncertain	0.46
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Benign	0.82	T;T
M_CAP	Uncertain	0.23	D
MetaRNN	Benign	0.26	T;T
MetaSVM	Uncertain	-0.24	T
MutationAssessor	Benign	1.0	.;L
PhyloP100		4.7
PROVEAN	Benign	-0.22	.;N
REVEL	Benign	0.20
Sift	Benign	0.53	.;T
Sift4G	Benign	0.20	.;T
Polyphen		0.46	.;P
Vest4		0.35
MutPred		0.30		.;Loss of stability (P = 0.1737);
MVP		0.043
ClinPred		0.54	D
GERP RS		5.7
Varity_R		0.17
gMVP		0.11
Mutation Taster		=77/23	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: rs1489662261; hg19: chr12-101316090;