Genetic Variant CSMD2:p.Arg2603Gln (chr1-33571681-C-T) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001281956.2(CSMD2):c.7808G>A(p.Arg2603Gln) variant causes a missense change. The variant allele was found at a frequency of 0.00000573 in 1,571,874 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. R2603L) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000056 ( 0 hom. )

Consequence

CSMD2
NM_001281956.2 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 6.16

Publications

4 publications found

Variant links:

Genes affected

CSMD2 (HGNC:19290): (CUB and Sushi multiple domains 2) The protein encoded by this gene is thought to be involved in the control of complement cascade of the immune system. Defects in this gene have been associated with schizophrenia. This gene may act as a tumor suppressor for colorectal cancer. [provided by RefSeq, Jan 2020]

CSMD2 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CSMD2	NM_001281956.2 link	c.7808G>A	p.Arg2603Gln	missense_variant	Exon 51 of 71	ENST00000373381.9	NP_001268885.1	Q7Z408-4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
CSMD2	ENST00000373381.9 link	c.7808G>A	p.Arg2603Gln	missense_variant	Exon 51 of 71	1	NM_001281956.2	ENSP00000362479.4	Q7Z408-4
CSMD2	ENST00000373388.7 link	c.7814G>A	p.Arg2605Gln	missense_variant	Exon 52 of 70	1		ENSP00000362486.3	Q7Z408-1
CSMD2	ENST00000619121.4 link	c.7688G>A	p.Arg2563Gln	missense_variant	Exon 51 of 71	5		ENSP00000483463.1	A0A087X0K4
CSMD2	ENST00000465819.1 link	c.131G>A	p.Arg44Gln	missense_variant	Exon 2 of 5	5		ENSP00000509557.1	A0A8I5KWH5

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152206

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00

AC:

AN:

244468

AF XY:

0.00

Gnomad AFR exome

AF:

0.00

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:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000564

AC:

AN:

1419668

Hom.:

Cov.:

AF XY:

0.00000712

AC XY:

AN XY:

702006

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32878

American (AMR)

AF:

0.00

AC:

AN:

43166

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25452

East Asian (EAS)

AF:

0.00

AC:

AN:

38724

South Asian (SAS)

AF:

0.0000127

AC:

AN:

78920

European-Finnish (FIN)

AF:

0.0000190

AC:

AN:

52610

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5518

European-Non Finnish (NFE)

AF:

0.00000461

AC:

AN:

1084124

Other (OTH)

AF:

0.0000172

AC:

AN:

58276

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.450

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152206

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74356

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41468

American (AMR)

AF:

0.00

AC:

AN:

15280

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5194

South Asian (SAS)

AF:

0.000207

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10612

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68032

Other (OTH)

AF:

0.00

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ExAC

AF:

0.00000824

AC:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Uncertain

0.031

BayesDel_noAF

Benign

-0.19

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.065

.;T;T

Eigen

Uncertain

0.55

Eigen_PC

Uncertain

0.59

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.96

D;D;D

M_CAP

Benign

0.029

MetaRNN

Uncertain

0.70

D;D;D

MetaSVM

Benign

-0.74

MutationAssessor

Benign

1.9

.;M;.

PhyloP100

6.2

PrimateAI

Uncertain

0.59

PROVEAN

Benign

-2.3

N;.;.

REVEL

Benign

0.26

Sift

Benign

0.21

T;.;.

Sift4G

Benign

0.081

T;T;T

Polyphen

0.99

.;D;.

Vest4

0.78

MutPred

0.65

.;Loss of catalytic residue at R2605 (P = 0.1652);.;

MVP

0.60

ClinPred

0.96

GERP RS

5.0

Varity_R

0.30

gMVP

0.47

Mutation Taster

=52/48

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over