chr13-27968589-G-C

Variant names:

• chr13-27968589-G-C
• rs1361731354
• NM_001265.6:c.418C>G

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 3P and 2B. PM2 PP2 BP4_Moderate

The NM_001265.6(CDX2):​c.418C>G​(p.Leu140Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,242 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
• Consequence: CDX2 NM_001265.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.39
• Publications: 1 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 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=0.26142293).

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.418C>G	p.Leu140Val	missense	Exon 1 of 3	NP_001256.4	Q99626
	CDX2	NM_001354700.2		c.418C>G	p.Leu140Val	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.418C>G	p.Leu140Val	missense	Exon 1 of 3	ENSP00000370408.6	Q99626
	CDX2	ENST00000891171.1		c.418C>G	p.Leu140Val	missense	Exon 1 of 3	ENSP00000561230.1
	CDX2	ENST00000947371.1		c.418C>G	p.Leu140Val	missense	Exon 2 of 4	ENSP00000617430.1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152242 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 31

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152242 Hom.: 0 Cov.: 33 AF XY: 0.0000134 AC XY: 1 AN XY: 74378

African (AFR) AF: 0.0000241 AC: 1 AN: 41466

American (AMR) AF: 0.00 AC: 0 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5194

South Asian (SAS) AF: 0.00 AC: 0 AN: 4838

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10628

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68038

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

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	Benign	0.083
BayesDel_addAF	Benign	-0.027	T
BayesDel_noAF	Benign	-0.28
CADD	Benign	20
DANN	Benign	0.78
DEOGEN2	Benign	0.20	T
Eigen	Benign	-0.47
Eigen_PC	Benign	-0.38
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Benign	0.58	T
M_CAP	Pathogenic	0.57	D
MetaRNN	Benign	0.26	T
MetaSVM	Benign	-0.51	T
MutationAssessor	Benign	1.3	L
PhyloP100		2.4
PrimateAI	Pathogenic	0.90	D
PROVEAN	Benign	-0.72	N
REVEL	Benign	0.24
Sift	Benign	0.30	T
Sift4G	Benign	0.82	T
Polyphen		0.11	B
Vest4		0.099
MutPred		0.59		Gain of catalytic residue at P144 (P = 5e-04)
MVP		0.74
MPC		0.77
ClinPred		0.58	D
GERP RS		3.9
Varity_R		0.21
gMVP		0.75
Mutation Taster		=85/15	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

dbSNP: rs1361731354; hg19: chr13-28542726;