3-86065706-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_001167675.2(CADM2):c.1072G>C(p.Gly358Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: CADM2 NM_001167675.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.19

Genes affected

CADM2 (HGNC:29849): (cell adhesion molecule 2) This gene encodes a member of the synaptic cell adhesion molecule 1 (SynCAM) family which belongs to the immunoglobulin (Ig) superfamily. The encoded protein has three Ig-like domains and a cytosolic protein 4.1 binding site near the C-terminus. Proteins belonging to the protein 4.1 family crosslink spectrin and interact with other cytoskeletal proteins. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Feb 2012]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.918

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CADM2	NM_001167675.2	c.1072G>C	p.Gly358Arg	missense_variant	9/10	ENST00000383699.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CADM2	ENST00000383699.8	c.1072G>C	p.Gly358Arg	missense_variant	9/10	1	NM_001167675.2	A1
CADM2	ENST00000405615.2	c.1171G>C	p.Gly391Arg	missense_variant	9/10	1
CADM2	ENST00000407528.6	c.1165G>C	p.Gly389Arg	missense_variant	9/10	1		P4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 18, 2023

The c.1171G>C (p.G391R) alteration is located in exon 9 (coding exon 9) of the CADM2 gene. This alteration results from a G to C substitution at nucleotide position 1171, causing the glycine (G) at amino acid position 391 to be replaced by an arginine (R). 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	0.95
BayesDel_addAF	Pathogenic	0.37	D
BayesDel_noAF	Pathogenic	0.29
Cadd	Pathogenic	29
Dann	Pathogenic	1.0
Eigen	Pathogenic	0.77
Eigen_PC	Pathogenic	0.77
FATHMM_MKL	Pathogenic	0.99	D
M_CAP	Uncertain	0.088	D
MetaRNN	Pathogenic	0.92	D;D;D
MetaSVM	Benign	-0.34	T
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Pathogenic	0.93	D
PROVEAN	Pathogenic	-5.5	D;D;D
REVEL	Pathogenic	0.72
Sift	Uncertain	0.013	D;D;D
Sift4G	Uncertain	0.0020	D;D;D
Polyphen		1.0	.;D;D
Vest4		0.89
MutPred		0.84		.;Gain of MoRF binding (P = 0.0325);.;
MVP		0.68
MPC		1.4
ClinPred		1.0	D
GERP RS		5.8
Varity_R		0.77
gMVP		0.83

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr3-86114856;