13-27963296-T-G

Variant names:

• chr13-27963296-T-G
• rs1284944894
• NM_001265.6:c.761A>C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001265.6(CDX2):​c.761A>C​(p.Gln254Pro) 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. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: CDX2 NM_001265.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.17

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.15894857).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CDX2	NM_001265.6	c.761A>C	p.Gln254Pro	missense_variant	Exon 3 of 3	ENST00000381020.8	NP_001256.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CDX2	ENST00000381020.8	c.761A>C	p.Gln254Pro	missense_variant	Exon 3 of 3	1	NM_001265.6	ENSP00000370408.6
CDX2	ENST00000548877.1	n.289A>C		non_coding_transcript_exon_variant	Exon 3 of 3	3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 36

GnomAD4 genome Cov.: 33

Bravo AF: 0.0000113

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Aug 18, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.761A>C (p.Q254P) alteration is located in exon 3 (coding exon 3) of the CDX2 gene. This alteration results from a A to C substitution at nucleotide position 761, causing the glutamine (Q) at amino acid position 254 to be replaced by a proline (P). 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	Benign	0.063
BayesDel_addAF	Uncertain	0.028	T
BayesDel_noAF	Benign	-0.20
CADD	Benign	17
DANN	Benign	0.95
DEOGEN2	Benign	0.40	T
Eigen	Benign	-0.084
Eigen_PC	Benign	0.0047
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.51	T
M_CAP	Benign	0.016	T
MetaRNN	Benign	0.16	T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	0.55	N
PrimateAI	Uncertain	0.55	T
PROVEAN	Benign	-1.4	N
REVEL	Benign	0.18
Sift	Benign	0.14	T
Sift4G	Benign	0.33	T
Polyphen		0.064	B
Vest4		0.25
MutPred		0.29		Gain of catalytic residue at P257 (P = 5e-04);
MVP		0.86
MPC		0.83
ClinPred		0.30	T
GERP RS		4.3
Varity_R		0.84
gMVP		0.73

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

LitVar

Other links and lift over

dbSNP: rs1284944894; hg19: chr13-28537433;