19-42583262-C-T

Variant names:

• chr19-42583262-C-T
• rs372343180
• NM_001816.4:c.1034G>A

Variant summary

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

The NM_001816.4(CEACAM8):​c.1034G>A​(p.Arg345Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000372 in 1,611,436 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: CEACAM8 NM_001816.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.0320

Genes affected

CEACAM8 (HGNC:1820): (CEA cell adhesion molecule 8) Enables protein heterodimerization activity. Involved in heterophilic cell-cell adhesion via plasma membrane cell adhesion molecules. Located in cell surface and extracellular space. Biomarker of severe acute respiratory syndrome. [provided by Alliance of Genome Resources, Apr 2022]

LIPE-AS1 (HGNC:48589): (LIPE antisense RNA 1)

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=0.057605892).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CEACAM8	NM_001816.4	c.1034G>A	p.Arg345Lys	missense_variant	Exon 5 of 6	ENST00000244336.10	NP_001807.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CEACAM8	ENST00000244336.10	c.1034G>A	p.Arg345Lys	missense_variant	Exon 5 of 6	1	NM_001816.4	ENSP00000244336.5

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152202 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

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 AF: 0.00000206 AC: 3 AN: 1459234 Hom.: 0 Cov.: 29 AF XY: 0.00000138 AC XY: 1 AN XY: 726140

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000270

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152202 Hom.: 0 Cov.: 31 AF XY: 0.0000403 AC XY: 3 AN XY: 74358

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.0000654

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: 0.0000151

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Sep 20, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1034G>A (p.R345K) alteration is located in exon 5 (coding exon 5) of the CEACAM8 gene. This alteration results from a G to A substitution at nucleotide position 1034, causing the arginine (R) at amino acid position 345 to be replaced by a lysine (K). 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	0.16
BayesDel_addAF	Benign	-0.35	T
BayesDel_noAF	Benign	-0.74
CADD	Benign	0.34
DANN	Benign	0.25
DEOGEN2	Benign	0.050	T;.
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.014	N
LIST_S2	Benign	0.28	T;T
M_CAP	Benign	0.0013	T
MetaRNN	Benign	0.058	T;T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	0.90	L;.
PrimateAI	Benign	0.24	T
PROVEAN	Benign	0.020	N;.
REVEL	Benign	0.050
Sift	Benign	1.0	T;.
Sift4G	Benign	0.094	T;D
Polyphen		0.13	B;.
Vest4		0.056
MutPred		0.55		Gain of ubiquitination at R345 (P = 0.0258);.;
MVP		0.11
MPC		0.020
ClinPred		0.047	T
GERP RS		-1.1
Varity_R		0.057
gMVP		0.39

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

Publications

LitVar

Other links and lift over

dbSNP: rs372343180; hg19: chr19-43087414;