Genetic Variant CDX2:p.Gly160Asp (chr13-27968528-C-T) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 3P and 2B. PM2PP2BP4_Moderate

The NM_001265.6(CDX2):c.479G>A(p.Gly160Asp) 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. 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. G160S) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

CDX2
NM_001265.6 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.905

Publications

0 publications found

Variant links:

Genes affected

CDX2 (HGNC:1806): (caudal type homeobox 2) This gene is a member of the caudal-related homeobox transcription factor gene family. The encoded protein is a major regulator of intestine-specific genes involved in cell growth an differentiation. This protein also plays a role in early embryonic development of the intestinal tract. Aberrant expression of this gene is associated with intestinal inflammation and tumorigenesis. [provided by RefSeq, Jan 2012]

CDX2 links:

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ACMG classification

Classification was made for transcript

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 1 curated pathogenic missense variants (we use a threshold of 10). The gene has 0 curated benign missense variants. Gene score misZ: 1.0581 (below the threshold of 3.09). Trascript score misZ: -0.02091 (below the threshold of 3.09).

BP4

Computational evidence support a benign effect (MetaRNN=0.21213979).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CDX2	NM_001265.6 link	c.479G>A	p.Gly160Asp	missense_variant	Exon 1 of 3	ENST00000381020.8	NP_001256.4	Q99626

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CDX2	ENST00000381020.8 link	c.479G>A	p.Gly160Asp	missense_variant	Exon 1 of 3	1	NM_001265.6	ENSP00000370408.6		Q99626

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1412108

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

702630

African (AFR)

AF:

0.00

AC:

AN:

29190

American (AMR)

AF:

0.00

AC:

AN:

40240

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24708

East Asian (EAS)

AF:

0.00

AC:

AN:

35178

South Asian (SAS)

AF:

0.00

AC:

AN:

82628

European-Finnish (FIN)

AF:

0.00

AC:

AN:

38206

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5166

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1098236

Other (OTH)

AF:

0.00

AC:

AN:

58556

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

May 24, 2023

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.479G>A (p.G160D) alteration is located in exon 1 (coding exon 1) of the CDX2 gene. This alteration results from a G to A substitution at nucleotide position 479, causing the glycine (G) at amino acid position 160 to be replaced by an aspartic acid (D). 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

Pathogenic

0.67

BayesDel_addAF

Benign

-0.17

BayesDel_noAF

Benign

-0.49

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.29

Eigen

Benign

-0.18

Eigen_PC

Benign

-0.11

FATHMM_MKL

Benign

0.62

LIST_S2

Benign

0.84

M_CAP

Uncertain

0.29

MetaRNN

Benign

0.21

MetaSVM

Benign

-0.98

MutationAssessor

Benign

1.4

PhyloP100

0.91

PrimateAI

Pathogenic

0.85

PROVEAN

Benign

-1.6

REVEL

Benign

0.12

Sift

Benign

0.21

Sift4G

Benign

0.65

Polyphen

0.39

Vest4

0.14

MutPred

0.45

Gain of catalytic residue at Q161 (P = 0.0086);

MVP

0.40

MPC

1.4

ClinPred

0.74

GERP RS

4.9

Varity_R

0.42

gMVP

0.79

Mutation Taster

=73/27

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over