19-41683989-A-C

Variant names:

• chr19-41683989-A-C
• rs1363541669
• NM_001291485.2:c.502T>G

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_001291485.2(CEACAM7):​c.502T>G​(p.Cys168Gly) variant causes a missense change. The variant allele was found at a frequency of 0.00000657 in 152,226 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
• Consequence: CEACAM7 NM_001291485.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.78

Genes affected

CEACAM7 (HGNC:1819): (CEA cell adhesion molecule 7) This gene encodes a cell surface glycoprotein and member of the carcinoembryonic antigen (CEA) family of proteins. Expression of this gene may be downregulated in colon and rectal cancer. Additionally, lower expression levels of this gene may be predictive of rectal cancer recurrence. This gene is present in a CEA family gene cluster on chromosome 19. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jul 2015]

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.972

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CEACAM7	NM_001291485.2	c.502T>G	p.Cys168Gly	missense_variant	Exon 3 of 5	ENST00000401731.6	NP_001278414.1
CEACAM7	NM_006890.5	c.502T>G	p.Cys168Gly	missense_variant	Exon 3 of 5		NP_008821.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CEACAM7	ENST00000401731.6	c.502T>G	p.Cys168Gly	missense_variant	Exon 3 of 5	2	NM_001291485.2	ENSP00000385932.1
CEACAM7	ENST00000006724.7	c.502T>G	p.Cys168Gly	missense_variant	Exon 3 of 5	1		ENSP00000006724.3
CEACAM7	ENST00000602225.1	c.427+2870T>G		intron_variant	Intron 2 of 2	1		ENSP00000469597.1
CEACAM7	ENST00000599715.1	n.*56T>G		downstream_gene_variant		5

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152226 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

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: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 32

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152226 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74360

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

May 29, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.502T>G (p.C168G) alteration is located in exon 3 (coding exon 3) of the CEACAM7 gene. This alteration results from a T to G substitution at nucleotide position 502, causing the cysteine (C) at amino acid position 168 to be replaced by a glycine (G). 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	0.93
BayesDel_addAF	Pathogenic	0.45	D
BayesDel_noAF	Pathogenic	0.42
CADD	Benign	21
DANN	Benign	0.86
Eigen	Uncertain	0.22
Eigen_PC	Benign	-0.097
FATHMM_MKL	Benign	0.38	N
M_CAP	Benign	0.061	D
MetaRNN	Pathogenic	0.97	D;D
MetaSVM	Uncertain	0.65	D
PrimateAI	Benign	0.45	T
PROVEAN	Pathogenic	-10	D;D
REVEL	Uncertain	0.64
Sift	Uncertain	0.0020	D;D
Sift4G	Uncertain	0.0030	D;D
Vest4		0.85
MutPred		0.82		Loss of sheet (P = 0.0126);Loss of sheet (P = 0.0126);
MVP		0.89
MPC		0.13
ClinPred		0.56	D
GERP RS		2.8
gMVP		0.88

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs1363541669; hg19: chr19-42187920;