16-288189-C-G

Variant names:

• chr16-288189-C-G
• NM_003502.4:c.2522G>C

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_003502.4(AXIN1):​c.2522G>C​(p.Arg841Pro) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,461,386 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: AXIN1 NM_003502.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.87

Genes affected

AXIN1 (HGNC:903): (axin 1) This gene encodes a cytoplasmic protein which contains a regulation of G-protein signaling (RGS) domain and a dishevelled and axin (DIX) domain. The encoded protein interacts with adenomatosis polyposis coli, catenin beta-1, glycogen synthase kinase 3 beta, protein phosphate 2, and itself. This protein functions as a negative regulator of the wingless-type MMTV integration site family, member 1 (WNT) signaling pathway and can induce apoptosis. The crystal structure of a portion of this protein, alone and in a complex with other proteins, has been resolved. Mutations in this gene have been associated with hepatocellular carcinoma, hepatoblastomas, ovarian endometriod adenocarcinomas, and medullablastomas. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jan 2016]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.817

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AXIN1	NM_003502.4	c.2522G>C	p.Arg841Pro	missense_variant	Exon 11 of 11	ENST00000262320.8	NP_003493.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AXIN1	ENST00000262320.8	c.2522G>C	p.Arg841Pro	missense_variant	Exon 11 of 11	1	NM_003502.4	ENSP00000262320.3
AXIN1	ENST00000354866.7	c.2414G>C	p.Arg805Pro	missense_variant	Exon 10 of 10	1		ENSP00000346935.3
AXIN1	ENST00000461023.5	n.5591G>C		non_coding_transcript_exon_variant	Exon 8 of 8	2
AXIN1	ENST00000457798.1	c.*27G>C		downstream_gene_variant		3		ENSP00000416835.1

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461386 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 726986

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 34

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.75
BayesDel_addAF	Uncertain	0.094	D
BayesDel_noAF	Benign	-0.10
CADD	Benign	23
DANN	Benign	0.96
DEOGEN2	Uncertain	0.68	D;.
Eigen	Uncertain	0.21
Eigen_PC	Benign	0.085
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.92	D;D
M_CAP	Uncertain	0.11	D
MetaRNN	Pathogenic	0.82	D;D
MetaSVM	Benign	-0.77	T
MutationAssessor	Uncertain	2.3	M;.
PrimateAI	Uncertain	0.51	T
PROVEAN	Uncertain	-2.8	D;D
REVEL	Benign	0.29
Sift	Benign	0.26	T;T
Sift4G	Benign	0.25	T;T
Polyphen		1.0	D;D
Vest4		0.72
MutPred		0.43		Gain of disorder (P = 0.0896);.;
MVP		0.56
MPC		1.3
ClinPred		0.92	D
GERP RS		4.4
Varity_R		0.92
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: chr16-338189;