chr13-27968469-G-T

Variant names:

• chr13-27968469-G-T
• NM_001265.6:c.538C>A

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.538C>A​(p.Gln180Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000717 in 1,394,370 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.2e-7 (0 hom.)
• Consequence: CDX2 NM_001265.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.878
• 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=0.3372237).

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.538C>A	p.Gln180Lys	missense	Exon 1 of 3	NP_001256.4	Q99626
	CDX2	NM_001354700.2		c.538C>A	p.Gln180Lys	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.538C>A	p.Gln180Lys	missense	Exon 1 of 3	ENSP00000370408.6	Q99626
	CDX2	ENST00000891171.1		c.538C>A	p.Gln180Lys	missense	Exon 1 of 3	ENSP00000561230.1
	CDX2	ENST00000947371.1		c.538C>A	p.Gln180Lys	missense	Exon 2 of 4	ENSP00000617430.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 7.17e-7 AC: 1 AN: 1394370 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 693450

African (AFR) AF: 0.00 AC: 0 AN: 28456

American (AMR) AF: 0.00 AC: 0 AN: 36710

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23742

East Asian (EAS) AF: 0.00 AC: 0 AN: 34340

South Asian (SAS) AF: 0.00 AC: 0 AN: 80062

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 37440

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4158

European-Non Finnish (NFE) AF: 9.16e-7 AC: 1 AN: 1091686

Other (OTH) AF: 0.00 AC: 0 AN: 57776

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	Benign	0.32
BayesDel_addAF	Uncertain	0.034	T
BayesDel_noAF	Benign	-0.19
CADD	Benign	22
DANN	Benign	0.96
DEOGEN2	Benign	0.33	T
Eigen	Benign	-0.15
Eigen_PC	Benign	-0.040
FATHMM_MKL	Benign	0.69	D
LIST_S2	Benign	0.65	T
M_CAP	Pathogenic	0.87	D
MetaRNN	Benign	0.34	T
MetaSVM	Uncertain	0.23	D
MutationAssessor	Benign	1.2	L
PhyloP100		0.88
PrimateAI	Pathogenic	0.82	D
PROVEAN	Benign	-0.72	N
REVEL	Uncertain	0.34
Sift	Benign	0.27	T
Sift4G	Benign	0.11	T
Polyphen		0.36	B
Vest4		0.12
MutPred		0.52		Gain of methylation at Q180 (P = 0.003)
MVP		0.78
MPC		1.2
ClinPred		0.39	T
GERP RS		4.9
Varity_R		0.30
gMVP		0.82
Mutation Taster		=89/11	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: chr13-28542606;