12-101020075-C-G

Variant names:

• chr12-101020075-C-G
• NM_001286615.2:c.776C>G

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP2

The NM_001286615.2(ANO4):​c.776C>G​(p.Thr259Arg) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. 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. T259A) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: ANO4 NM_001286615.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.54
• 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 3 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001286615.2. 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
	ANO4	NM_001286615.2	MANE Select	c.776C>G	p.Thr259Arg	missense	Exon 9 of 28	NP_001273544.1	Q32M45-1
	ANO4	NM_001286616.1		c.776C>G	p.Thr259Arg	missense	Exon 8 of 27	NP_001273545.1	Q32M45-1
	ANO4	NM_178826.4		c.671C>G	p.Thr224Arg	missense	Exon 8 of 27	NP_849148.2	Q32M45-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ANO4	ENST00000392977.8	TSL:2 MANE Select	c.776C>G	p.Thr259Arg	missense	Exon 9 of 28	ENSP00000376703.3	Q32M45-1
	ANO4	ENST00000644049.1		c.1274C>G	p.Thr425Arg	missense	Exon 11 of 30	ENSP00000494481.1	A0A2R8Y532
	ANO4	ENST00000852684.1		c.776C>G	p.Thr259Arg	missense	Exon 9 of 28	ENSP00000522743.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

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	Pathogenic	0.90
BayesDel_addAF	Pathogenic	0.33	D
BayesDel_noAF	Pathogenic	0.24
CADD	Pathogenic	27
DANN	Uncertain	0.99
DEOGEN2	Benign	0.26	T
Eigen	Pathogenic	0.87
Eigen_PC	Pathogenic	0.84
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Uncertain	0.11	D
MetaRNN	Uncertain	0.72	D
MetaSVM	Uncertain	0.27	D
MutationAssessor	Pathogenic	3.3	M
PhyloP100		5.5
PrimateAI	Pathogenic	0.83	D
PROVEAN	Uncertain	-3.6	D
REVEL	Uncertain	0.57
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.0080	D
Polyphen		1.0	D
Vest4		0.88
MutPred		0.36		Gain of MoRF binding (P = 0.0164)
MVP		0.24
MPC		1.6
ClinPred		0.99	D
GERP RS		5.8
Varity_R		0.88
gMVP		0.86
Mutation Taster		=36/64	disease causing

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

hg19: chr12-101413853;