NM_001265.6:c.335A>C

Variant names:

• chr13-27968672-T-G
• NM_001265.6:c.335A>C

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 3P and 1B. PM2 PP2 BP4

The NM_001265.6(CDX2):​c.335A>C​(p.Asp112Ala) 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. 13/22 in silico tools predict 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. D112N) has been classified 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: 1.64
• Publications: 0 publications found

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

Our verdict: Uncertain_significance. The variant received 2 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=0.32210082).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001265.6. 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
	CDX2	NM_001265.6	MANE Select	c.335A>C	p.Asp112Ala	missense	Exon 1 of 3	NP_001256.4	Q99626
	CDX2	NM_001354700.2		c.335A>C	p.Asp112Ala	missense	Exon 1 of 3	NP_001341629.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CDX2	ENST00000381020.8	TSL:1 MANE Select	c.335A>C	p.Asp112Ala	missense	Exon 1 of 3	ENSP00000370408.6	Q99626
	CDX2	ENST00000891171.1		c.335A>C	p.Asp112Ala	missense	Exon 1 of 3	ENSP00000561230.1
	CDX2	ENST00000947371.1		c.335A>C	p.Asp112Ala	missense	Exon 2 of 4	ENSP00000617430.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

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	Uncertain	0.50
BayesDel_addAF	Benign	-0.080	T
BayesDel_noAF	Benign	-0.35
CADD	Benign	21
DANN	Benign	0.95
DEOGEN2	Benign	0.35	T
Eigen	Benign	-0.48
Eigen_PC	Benign	-0.44
FATHMM_MKL	Benign	0.74	D
LIST_S2	Benign	0.59	T
M_CAP	Pathogenic	0.40	D
MetaRNN	Benign	0.32	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Uncertain	2.4	M
PhyloP100		1.6
PrimateAI	Pathogenic	0.93	D
PROVEAN	Benign	-2.0	N
REVEL	Benign	0.17
Sift	Benign	0.22	T
Sift4G	Benign	0.083	T
Polyphen		0.15	B
Vest4		0.22
MutPred		0.59		Gain of catalytic residue at Y107 (P = 5e-04)
MVP		0.58
MPC		0.89
ClinPred		0.51	D
GERP RS		4.5
Varity_R		0.19
gMVP		0.74
Mutation Taster		=86/14	polymorphism

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: chr13-28542809;