3-85883396-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_001167675.2(CADM2):c.344T>C(p.Leu115Ser) 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. 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: 7.67

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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.82

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CADM2	NM_001167675.2	c.344T>C	p.Leu115Ser	missense_variant	4/10	ENST00000383699.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CADM2	ENST00000383699.8	c.344T>C	p.Leu115Ser	missense_variant	4/10	1	NM_001167675.2	A1
CADM2	ENST00000405615.2	c.323T>C	p.Leu108Ser	missense_variant	3/10	1
CADM2	ENST00000407528.6	c.317T>C	p.Leu106Ser	missense_variant	3/10	1		P4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251032 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135686

Gnomad AFR exome AF: 0.0000616

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000756

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00000824 AC: 1

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

Aug 12, 2021

The c.323T>C (p.L108S) alteration is located in exon 3 (coding exon 3) of the CADM2 gene. This alteration results from a T to C substitution at nucleotide position 323, causing the leucine (L) at amino acid position 108 to be replaced by a serine (S). 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	0.96
BayesDel_addAF	Benign	-0.052	T
BayesDel_noAF	Benign	-0.13
Cadd	Pathogenic	31
Dann	Uncertain	1.0
Eigen	Uncertain	0.56
Eigen_PC	Uncertain	0.47
FATHMM_MKL	Pathogenic	0.97	D
M_CAP	Benign	0.075	D
MetaRNN	Pathogenic	0.82	D;D;D
MetaSVM	Benign	-0.84	T
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Pathogenic	0.90	D
PROVEAN	Pathogenic	-4.8	D;D;D
REVEL	Uncertain	0.41
Sift	Pathogenic	0.0	D;D;D
Sift4G	Pathogenic	0.0010	D;D;D
Polyphen		1.0	.;D;D
Vest4		0.86
MVP		0.45
MPC		1.5
ClinPred		0.99	D
GERP RS		4.4
Varity_R		0.78
gMVP		0.94

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: rs138108612; hg19: chr3-85932546;