3-85979226-A-T

Variant names:

• chr3-85979226-A-T
• rs1408760706
• ENST00000405615.2:c.1012A>T

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_001375960.1(CADM2):​c.1033A>T​(p.Thr345Ser) variant causes a missense change. The variant allele was found at a frequency of 0.000000685 in 1,459,136 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T345A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: CADM2 NM_001375960.1 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.37
• Publications: 0 publications found

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

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.776

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001375960.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CADM2	NM_001167675.2	MANE Select	c.970+17579A>T		intron	N/A	NP_001161147.1	Q8N3J6-2
	CADM2	NM_001375960.1		c.1033A>T	p.Thr345Ser	missense	Exon 9 of 11	NP_001362889.1
	CADM2	NM_153184.4		c.1012A>T	p.Thr338Ser	missense	Exon 8 of 10	NP_694854.2	Q8N3J6-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CADM2	ENST00000405615.2	TSL:1	c.1012A>T	p.Thr338Ser	missense	Exon 8 of 10	ENSP00000384193.2	Q8N3J6-3
	CADM2	ENST00000407528.6	TSL:1	c.1006A>T	p.Thr336Ser	missense	Exon 8 of 10	ENSP00000384575.2	Q8N3J6-1
	CADM2	ENST00000383699.8	TSL:1 MANE Select	c.970+17579A>T		intron	N/A	ENSP00000373200.3	Q8N3J6-2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1459136 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 725920

African (AFR) AF: 0.00 AC: 0 AN: 33260

American (AMR) AF: 0.00 AC: 0 AN: 44640

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26006

East Asian (EAS) AF: 0.00 AC: 0 AN: 39632

South Asian (SAS) AF: 0.00 AC: 0 AN: 86148

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53394

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5746

European-Non Finnish (NFE) AF: 9.01e-7 AC: 1 AN: 1110094

Other (OTH) AF: 0.00 AC: 0 AN: 60216

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.090
BayesDel_addAF	Uncertain	0.029	T
BayesDel_noAF	Benign	-0.20
CADD	Benign	19
DANN	Benign	0.97
DEOGEN2	Benign	0.021	T
Eigen	Uncertain	0.39
Eigen_PC	Uncertain	0.46
FATHMM_MKL	Uncertain	0.96	D
M_CAP	Benign	0.018	T
MetaRNN	Pathogenic	0.78	D
MetaSVM	Benign	-0.70	T
MutationAssessor	Benign	0.0	N
PhyloP100		6.4
PrimateAI	Uncertain	0.61	T
PROVEAN	Benign	-0.88	N
REVEL	Benign	0.24
Sift	Benign	0.17	T
Sift4G	Benign	0.45	T
Polyphen		0.96	P
Vest4		0.74
MutPred		0.33		Loss of glycosylation at T336 (P = 0.0071)
MVP		0.61
MPC		0.37
ClinPred		0.79	D
GERP RS		5.3
Varity_R		0.11
gMVP		0.47
Mutation Taster		=85/15	polymorphism

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

Other links and lift over

dbSNP: rs1408760706; hg19: chr3-86028376;