12-101043631-C-G

Position:

• chr12-101043631-C-G

Variant summary

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

The NM_001286615.2(ANO4):​c.1247C>G​(p.Ala416Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar 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: 7.91

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ANO4	NM_001286615.2	c.1247C>G	p.Ala416Gly	missense_variant	13/28	ENST00000392977.8	NP_001273544.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ANO4	ENST00000392977.8	c.1247C>G	p.Ala416Gly	missense_variant	13/28	2	NM_001286615.2	ENSP00000376703
ANO4	ENST00000644049.1	c.1745C>G	p.Ala582Gly	missense_variant	15/30			ENSP00000494481
ANO4	ENST00000392979.7	c.1142C>G	p.Ala381Gly	missense_variant	12/27	2		ENSP00000376705	P1
ANO4	ENST00000548940.1	n.182C>G		non_coding_transcript_exon_variant	2/4	4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 28

GnomAD4 genome Cov.: 32

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

May 30, 2024

The c.1142C>G (p.A381G) alteration is located in exon 12 (coding exon 11) of the ANO4 gene. This alteration results from a C to G substitution at nucleotide position 1142, causing the alanine (A) at amino acid position 381 to be replaced by a glycine (G). 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	Uncertain	0.50
BayesDel_addAF	Pathogenic	0.23	D
BayesDel_noAF	Uncertain	0.10
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.43	.;.;T
Eigen	Pathogenic	0.81
Eigen_PC	Pathogenic	0.76
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Pathogenic	0.98	D;D;D
M_CAP	Benign	0.041	D
MetaRNN	Uncertain	0.72	D;D;D
MetaSVM	Uncertain	0.18	D
MutationAssessor	Uncertain	2.8	.;.;M
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Pathogenic	0.87	D
PROVEAN	Benign	-2.3	.;N;N
REVEL	Uncertain	0.57
Sift	Uncertain	0.0080	.;D;D
Sift4G	Uncertain	0.017	.;D;D
Polyphen		0.98, 0.99	.;D;D
Vest4		0.63, 0.63
MutPred		0.56		.;.;Loss of stability (P = 0.0476);
MVP		0.11
MPC		1.5
ClinPred		0.99	D
GERP RS		5.3
Varity_R		0.47
gMVP		0.80

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr12-101437409;