1-33527252-C-T

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 1P and 10B. PP2 BP4_Strong BP6_Moderate BS2

The NM_001281956.2(CSMD2):c.10178G>A(p.Arg3393Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00045 in 1,612,822 control chromosomes in the GnomAD database, including 23 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.00022 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00047 (23 hom.)
• Consequence: CSMD2 NM_001281956.2 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 3.38

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]

ACMG classification

Verdict is Benign. Variant got -9 ACMG points.

• PP2: Missense variant where missense usually causes diseases, CSMD2
• BP4: Computational evidence support a benign effect (MetaRNN=0.008602709).
• BP6: Variant 1-33527252-C-T is Benign according to our data. Variant chr1-33527252-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 2638623.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Homozygotes in GnomAdExome at 5 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CSMD2	NM_001281956.2	c.10178G>A	p.Arg3393Gln	missense_variant	65/71	ENST00000373381.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CSMD2	ENST00000373381.9	c.10178G>A	p.Arg3393Gln	missense_variant	65/71	1	NM_001281956.2	P2
CSMD2	ENST00000373388.7	c.9746G>A	p.Arg3249Gln	missense_variant	64/70	1
CSMD2	ENST00000619121.4	c.10058G>A	p.Arg3353Gln	missense_variant	65/71	5		A2

Frequencies

GnomAD3 genomes AF: 0.000223 AC: 34 AN: 152142 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00477

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000893 AC: 223 AN: 249642 Hom.: 5 AF XY: 0.00114 AC XY: 154 AN XY: 134792

Gnomad AFR exome AF: 0.0000617

Gnomad AMR exome AF: 0.000175

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000545

Gnomad SAS exome AF: 0.00594

Gnomad FIN exome AF: 0.0000463

Gnomad NFE exome AF: 0.000239

Gnomad OTH exome AF: 0.00115

GnomAD4 exome AF: 0.000474 AC: 692 AN: 1460562 Hom.: 23 Cov.: 30 AF XY: 0.000654 AC XY: 475 AN XY: 726498

Gnomad4 AFR exome AF: 0.0000599

Gnomad4 AMR exome AF: 0.000225

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.00530

Gnomad4 FIN exome AF: 0.0000562

Gnomad4 NFE exome AF: 0.000166

Gnomad4 OTH exome AF: 0.000580

GnomAD4 genome AF: 0.000223 AC: 34 AN: 152260 Hom.: 0 Cov.: 32 AF XY: 0.000269 AC XY: 20 AN XY: 74462

Gnomad4 AFR AF: 0.000120

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00477

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000588

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.0000971 Hom.: 0

Bravo AF: 0.000102

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.000980 AC: 119

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.000218

EpiControl AF: 0.000178

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

May 01, 2023

CSMD2: BS2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.096
BayesDel_addAF	Benign	-0.45	T
BayesDel_noAF	Benign	-0.42
Cadd	Benign	23
Dann	Uncertain	1.0
Eigen	Benign	0.085
Eigen_PC	Uncertain	0.25
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.86	D;D;D
M_CAP	Benign	0.0079	T
MetaRNN	Benign	0.0086	T;T;T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.58	T
PROVEAN	Benign	-0.78	N;.;.
REVEL	Benign	0.036
Sift	Benign	0.29	T;.;.
Sift4G	Benign	0.43	T;T;T
Polyphen		0.080	.;B;.
Vest4		0.59
MVP		0.37
ClinPred		0.017	T
GERP RS		5.4
Varity_R		0.13
gMVP		0.41

Splicing

Name	Calibrated prediction	Score	Prediction
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

Publications

LitVar

Other links and lift over

dbSNP: rs148437366; hg19: chr1-33992852;