rs145452087

Variant names:

• chr3-86065607-C-T
• rs145452087
• NM_001167675.2:c.973C>T

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BS2

The NM_001167675.2(CADM2):​c.973C>T​(p.Pro325Ser) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000757 in 1,611,532 control chromosomes in the GnomAD database, with no homozygous occurrence. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000046 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000079 (0 hom.)
• Consequence: CADM2 NM_001167675.2 missense, splice_region
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.91
• 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: Likely_benign. The variant received -4 ACMG points.

• BS2: High AC in GnomAd4 at 7 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001167675.2. 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.973C>T	p.Pro325Ser	missense splice_region	Exon 9 of 10	NP_001161147.1	Q8N3J6-2
	CADM2	NM_001375960.1		c.1093C>T	p.Pro365Ser	missense splice_region	Exon 10 of 11	NP_001362889.1
	CADM2	NM_153184.4		c.1072C>T	p.Pro358Ser	missense splice_region	Exon 9 of 10	NP_694854.2	Q8N3J6-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CADM2	ENST00000383699.8	TSL:1 MANE Select	c.973C>T	p.Pro325Ser	missense splice_region	Exon 9 of 10	ENSP00000373200.3	Q8N3J6-2
	CADM2	ENST00000405615.2	TSL:1	c.1072C>T	p.Pro358Ser	missense splice_region	Exon 9 of 10	ENSP00000384193.2	Q8N3J6-3
	CADM2	ENST00000407528.6	TSL:1	c.1066C>T	p.Pro356Ser	missense splice_region	Exon 9 of 10	ENSP00000384575.2	Q8N3J6-1

Frequencies

GnomAD3 genomes AF: 0.0000460 AC: 7 AN: 152194 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.0000882

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000402 AC: 10 AN: 248614 AF XY: 0.0000372

Gnomad AFR exome AF: 0.0000618

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000799

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000788 AC: 115 AN: 1459338 Hom.: 0 Cov.: 30 AF XY: 0.0000771 AC XY: 56 AN XY: 725948

African (AFR) AF: 0.0000300 AC: 1 AN: 33328

American (AMR) AF: 0.00 AC: 0 AN: 44140

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25994

East Asian (EAS) AF: 0.00 AC: 0 AN: 39560

South Asian (SAS) AF: 0.00 AC: 0 AN: 85780

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53386

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5752

European-Non Finnish (NFE) AF: 0.000101 AC: 112 AN: 1111118

Other (OTH) AF: 0.0000332 AC: 2 AN: 60280

GnomAD4 genome AF: 0.0000460 AC: 7 AN: 152194 Hom.: 0 Cov.: 32 AF XY: 0.0000404 AC XY: 3 AN XY: 74340

African (AFR) AF: 0.0000241 AC: 1 AN: 41458

American (AMR) AF: 0.00 AC: 0 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10610

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000882 AC: 6 AN: 68038

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.000130 Hom.: 0

Bravo AF: 0.0000453

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.0000330 AC: 4

EpiCase AF: 0.00

EpiControl AF: 0.0000596

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.094
BayesDel_addAF	Uncertain	0.10	D
BayesDel_noAF	Uncertain	0.10
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.022	T
Eigen	Pathogenic	0.72
Eigen_PC	Pathogenic	0.76
FATHMM_MKL	Pathogenic	0.98	D
M_CAP	Benign	0.081	D
MetaRNN	Uncertain	0.66	D
MetaSVM	Uncertain	0.45	D
MutationAssessor	Benign	0.97	L
PhyloP100		7.9
PrimateAI	Uncertain	0.57	T
PROVEAN	Uncertain	-4.3	D
REVEL	Uncertain	0.35
Sift	Benign	0.062	T
Sift4G	Benign	0.082	T
Polyphen		1.0	D
Vest4		0.81
MVP		0.59
MPC		1.0
ClinPred		0.42	T
GERP RS		5.8
Varity_R		0.15
gMVP		0.75
Mutation Taster		=18/82	disease causing

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: rs145452087; hg19: chr3-86114757; COSMIC: COSV105310761;