Variant chr1-33519675-C-G details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_001281956.2(CSMD2):c.10739G>C(p.Arg3580Thr) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000508 in 1,613,948 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00028 ( 0 hom., cov: 31)

Exomes 𝑓: 0.000027 ( 0 hom. )

Consequence

CSMD2
NM_001281956.2 missense, splice_region

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.94

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.02838707).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CSMD2	NM_001281956.2 linkuse as main transcript	c.10739G>C	p.Arg3580Thr	missense_variant, splice_region_variant	70/71	ENST00000373381.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CSMD2	ENST00000373381.9 linkuse as main transcript	c.10739G>C	p.Arg3580Thr	missense_variant, splice_region_variant	70/71	1	NM_001281956.2	P2	Q7Z408-4
CSMD2	ENST00000373388.7 linkuse as main transcript	c.10307G>C	p.Arg3436Thr	missense_variant, splice_region_variant	69/70	1			Q7Z408-1
CSMD2	ENST00000619121.4 linkuse as main transcript	c.10619G>C	p.Arg3540Thr	missense_variant, splice_region_variant	70/71	5		A2

Frequencies

GnomAD3 genomes

AF:

0.000283

AC:

AN:

151982

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000991

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000557

AC:

AN:

251256

Hom.:

AF XY:

0.0000515

AC XY:

AN XY:

135800

show subpopulations

Gnomad AFR exome

AF:

0.000861

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS 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:

0.0000267

AC:

AN:

1461848

Hom.:

Cov.:

AF XY:

0.0000275

AC XY:

AN XY:

727220

show subpopulations

Gnomad4 AFR exome

AF:

0.000836

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.000116

GnomAD4 genome

AF:

0.000283

AC:

AN:

152100

Hom.:

Cov.:

AF XY:

0.000256

AC XY:

AN XY:

74342

show subpopulations

Gnomad4 AFR

AF:

0.000988

Gnomad4 AMR

AF:

0.0000654

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000142

Hom.:

Bravo

AF:

0.000329

ESP6500AA

AF:

0.000681

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000107

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 18, 2021

The c.10307G>C (p.R3436T) alteration is located in exon 69 (coding exon 69) of the CSMD2 gene. This alteration results from a G to C substitution at nucleotide position 10307, causing the arginine (R) at amino acid position 3436 to be replaced by a threonine (T). 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

Pathogenic

0.59

BayesDel_addAF

Benign

-0.40

BayesDel_noAF

Benign

-0.42

CADD

Benign

DANN

Benign

0.80

DEOGEN2

Benign

0.014

.;T;T

Eigen

Benign

-0.27

Eigen_PC

Benign

-0.045

FATHMM_MKL

Uncertain

0.94

LIST_S2

Benign

0.77

T;T;T

M_CAP

Benign

0.013

MetaRNN

Benign

0.028

T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.67

.;N;.

MutationTaster

Benign

1.0

PrimateAI

Pathogenic

0.91

PROVEAN

Benign

1.3

N;.;.

REVEL

Benign

0.096

Sift

Benign

0.70

T;.;.

Sift4G

Benign

0.58

T;T;T

Polyphen

0.017

.;B;.

Vest4

0.45

MVP

0.35

ClinPred

0.065

GERP RS

4.9

Varity_R

0.26

gMVP

0.35

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over