Genetic Variant CADM2:p.Pro267Leu (chr3-85961477-C-T) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001167675.2(CADM2):c.800C>T(p.Pro267Leu) variant causes a missense change. The variant allele was found at a frequency of 0.000000694 in 1,441,068 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

CADM2
NM_001167675.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.70

Variant links:

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]

CADM2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.23276907).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CADM2	NM_001167675.2 link	c.800C>T	p.Pro267Leu	missense_variant	Exon 8 of 10	ENST00000383699.8	NP_001161147.1	Q8N3J6-2G3XHN4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
CADM2	ENST00000383699.8 link	c.800C>T	p.Pro267Leu	missense_variant	Exon 8 of 10	1	NM_001167675.2	ENSP00000373200.3	Q8N3J6-2
CADM2	ENST00000405615.2 link	c.779C>T	p.Pro260Leu	missense_variant	Exon 7 of 10	1		ENSP00000384193.2	Q8N3J6-3
CADM2	ENST00000407528.6 link	c.773C>T	p.Pro258Leu	missense_variant	Exon 7 of 10	1		ENSP00000384575.2	Q8N3J6-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.94e-7

AC:

AN:

1441068

Hom.:

Cov.:

AF XY:

0.00000140

AC XY:

AN XY:

715646

show subpopulations

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:

9.12e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Nov 15, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.779C>T (p.P260L) alteration is located in exon 7 (coding exon 7) of the CADM2 gene. This alteration results from a C to T substitution at nucleotide position 779, causing the proline (P) at amino acid position 260 to be replaced by a leucine (L). 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

0.28

BayesDel_addAF

Uncertain

0.043

BayesDel_noAF

Benign

-0.18

CADD

Uncertain

DANN

Benign

0.97

DEOGEN2

Benign

0.024

.;T;.

Eigen

Benign

-0.085

Eigen_PC

Benign

0.16

FATHMM_MKL

Pathogenic

0.97

M_CAP

Benign

0.041

MetaRNN

Benign

0.23

T;T;T

MetaSVM

Benign

-0.72

MutationAssessor

Benign

-0.090

.;N;.

PrimateAI

Pathogenic

0.80

PROVEAN

Uncertain

-2.4

N;N;N

REVEL

Benign

0.22

Sift

Benign

0.25

T;T;T

Sift4G

Benign

0.33

T;T;T

Polyphen

0.071, 0.0090

.;B;B

Vest4

0.48

MutPred

0.67

.;Loss of disorder (P = 0.0139);.;

MVP

0.18

MPC

0.43

ClinPred

0.67

GERP RS

5.4

Varity_R

0.18

gMVP

0.82

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over