rs189908189

Variant names:

• chr3-85979286-A-G
• rs189908189
• NM_001167675.2:c.970+17639A>G

Your query was ambiguous. Multiple possible variants found:

• chr3-85979286-A-G
• chr3-85979286-A-C

Variant summary

Our verdict is Benign. The variant received -15 ACMG points: 1P and 16B. PP3 BP6_Very_Strong BS1 BS2

The NM_001375960.1(CADM2):​c.1090+3A>G variant causes a splice region, intron change. The variant allele was found at a frequency of 0.00306 in 1,609,828 control chromosomes in the GnomAD database, including 34 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0021 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0032 (34 hom.)
• Consequence: CADM2 NM_001375960.1 splice_region, intron
• Scores: Splicing: ADA: 0.9987
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• 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: Benign. The variant received -15 ACMG points.

• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.
• BP6: Variant 3-85979286-A-G is Benign according to our data. Variant chr3-85979286-A-G is described in ClinVar as Benign. ClinVar VariationId is 714392.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00212 (321/151766) while in subpopulation SAS AF = 0.0232 (112/4826). AF 95% confidence interval is 0.0197. There are 0 homozygotes in GnomAd4. There are 181 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 321 AD gene.

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+17639A>G		intron	N/A	NP_001161147.1	Q8N3J6-2
	CADM2	NM_001375960.1		c.1090+3A>G		splice_region intron	N/A	NP_001362889.1
	CADM2	NM_153184.4		c.1069+3A>G		splice_region intron	N/A	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.970+17639A>G		intron	N/A	ENSP00000373200.3	Q8N3J6-2
	CADM2	ENST00000405615.2	TSL:1	c.1069+3A>G		splice_region intron	N/A	ENSP00000384193.2	Q8N3J6-3
	CADM2	ENST00000407528.6	TSL:1	c.1063+3A>G		splice_region intron	N/A	ENSP00000384575.2	Q8N3J6-1

Frequencies

GnomAD3 genomes AF: 0.00212 AC: 322 AN: 151648 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000435

Gnomad AMI AF: 0.00329

Gnomad AMR AF: 0.000462

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0234

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00263

Gnomad OTH AF: 0.00144

GnomAD2 exomes AF: 0.00321 AC: 804 AN: 250510 AF XY: 0.00398

Gnomad AFR exome AF: 0.000372

Gnomad AMR exome AF: 0.000436

Gnomad ASJ exome AF: 0.000299

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.0000463

Gnomad NFE exome AF: 0.00214

Gnomad OTH exome AF: 0.00213

GnomAD4 exome AF: 0.00316 AC: 4601 AN: 1458062 Hom.: 34 Cov.: 30 AF XY: 0.00352 AC XY: 2551 AN XY: 725378

African (AFR) AF: 0.000361 AC: 12 AN: 33226

American (AMR) AF: 0.000426 AC: 19 AN: 44614

Ashkenazi Jewish (ASJ) AF: 0.0000771 AC: 2 AN: 25932

East Asian (EAS) AF: 0.00 AC: 0 AN: 39606

South Asian (SAS) AF: 0.0164 AC: 1410 AN: 86034

European-Finnish (FIN) AF: 0.000187 AC: 10 AN: 53360

Middle Eastern (MID) AF: 0.00105 AC: 6 AN: 5736

European-Non Finnish (NFE) AF: 0.00269 AC: 2981 AN: 1109422

Other (OTH) AF: 0.00268 AC: 161 AN: 60132

GnomAD4 genome AF: 0.00212 AC: 321 AN: 151766 Hom.: 0 Cov.: 32 AF XY: 0.00244 AC XY: 181 AN XY: 74156

African (AFR) AF: 0.000434 AC: 18 AN: 41484

American (AMR) AF: 0.000462 AC: 7 AN: 15156

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3458

East Asian (EAS) AF: 0.00 AC: 0 AN: 5128

South Asian (SAS) AF: 0.0232 AC: 112 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00263 AC: 178 AN: 67784

Other (OTH) AF: 0.00143 AC: 3 AN: 2104

Alfa AF: 0.00177 Hom.: 0

Bravo AF: 0.00142

Asia WGS AF: 0.00520 AC: 18 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.38
CADD	Uncertain	24
DANN	Benign	0.95
PhyloP100		6.4
Mutation Taster		=84/16	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.86
SpliceAI score (max)		0.16		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: rs189908189; hg19: chr3-86028436; COSMIC: COSV67363211;