19-41625637-C-T

Variant names:

• chr19-41625637-C-T
• rs200115429
• NM_001817.4:c.388G>A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001817.4(CEACAM4):​c.388G>A​(p.Asp130Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000416 in 1,441,650 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000042 (0 hom.)
• Consequence: CEACAM4 NM_001817.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -1.49

Genes affected

CEACAM4 (HGNC:1816): (CEA cell adhesion molecule 4) Involved in phagocytosis. Predicted to be located in extracellular region. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.060759038).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CEACAM4	NM_001817.4	c.388G>A	p.Asp130Asn	missense_variant	Exon 2 of 7	ENST00000221954.7	NP_001808.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CEACAM4	ENST00000221954.7	c.388G>A	p.Asp130Asn	missense_variant	Exon 2 of 7	1	NM_001817.4	ENSP00000221954.2
CEACAM4	ENST00000600925.1	c.388G>A	p.Asp130Asn	missense_variant	Exon 2 of 6	2		ENSP00000473018.1
CEACAM4	ENST00000472081.1	n.499G>A		non_coding_transcript_exon_variant	Exon 2 of 2	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000416 AC: 6 AN: 1441650 Hom.: 0 Cov.: 33 AF XY: 0.00000699 AC XY: 5 AN XY: 714944

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000253

Gnomad4 SAS exome AF: 0.0000242

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000182

Gnomad4 OTH exome AF: 0.0000168

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000756

ExAC AF: 0.0000165 AC: 2

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Mar 21, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.388G>A (p.D130N) alteration is located in exon 2 (coding exon 2) of the CEACAM4 gene. This alteration results from a G to A substitution at nucleotide position 388, causing the aspartic acid (D) at amino acid position 130 to be replaced by an asparagine (N). 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	0.092
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.69
CADD	Benign	7.8
DANN	Benign	0.91
DEOGEN2	Benign	0.0022	T;.
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.00072	N
M_CAP	Benign	0.0027	T
MetaRNN	Benign	0.061	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.84	L;.
PrimateAI	Benign	0.40	T
PROVEAN	Benign	-0.74	N;.
REVEL	Benign	0.12
Sift	Benign	0.49	T;.
Sift4G	Benign	0.40	T;T
Polyphen		0.98	D;.
Vest4		0.095
MutPred		0.25		Loss of catalytic residue at D130 (P = 0.1354);Loss of catalytic residue at D130 (P = 0.1354);
MVP		0.11
MPC		0.030
ClinPred		0.18	T
GERP RS		-3.6
Varity_R		0.074
gMVP		0.081

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs200115429; hg19: chr19-42132011; COSMIC: COSV55731905;