1-33521486-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP2 PP3

The NM_001281956.2(CSMD2):c.10574G>A(p.Gly3525Glu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000011 in 1,461,098 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000011 (0 hom.)
• Consequence: CSMD2 NM_001281956.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.57

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 Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, CSMD2
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.836

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CSMD2	NM_001281956.2	c.10574G>A	p.Gly3525Glu	missense_variant	68/71	ENST00000373381.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CSMD2	ENST00000373381.9	c.10574G>A	p.Gly3525Glu	missense_variant	68/71	1	NM_001281956.2	P2
CSMD2	ENST00000373388.7	c.10142G>A	p.Gly3381Glu	missense_variant	67/70	1
CSMD2	ENST00000619121.4	c.10454G>A	p.Gly3485Glu	missense_variant	68/71	5		A2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251472 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135906

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 SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000879

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000110 AC: 16 AN: 1461098 Hom.: 0 Cov.: 31 AF XY: 0.00000413 AC XY: 3 AN XY: 726976

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000144

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000312 Hom.: 0

Bravo AF: 0.00000756

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 29, 2023

The c.10142G>A (p.G3381E) alteration is located in exon 67 (coding exon 67) of the CSMD2 gene. This alteration results from a G to A substitution at nucleotide position 10142, causing the glycine (G) at amino acid position 3381 to be replaced by a glutamic acid (E). 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	0.62
BayesDel_addAF	Uncertain	0.14	D
BayesDel_noAF	Uncertain	-0.040
Cadd	Uncertain	25
Dann	Uncertain	1.0
Eigen	Pathogenic	0.72
Eigen_PC	Pathogenic	0.76
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.90	D;D;D
M_CAP	Benign	0.057	D
MetaRNN	Pathogenic	0.84	D;D;D
MetaSVM	Benign	-0.61	T
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.76	T
PROVEAN	Pathogenic	-6.9	D;.;.
REVEL	Uncertain	0.38
Sift	Pathogenic	0.0	D;.;.
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		1.0	.;D;.
Vest4		0.90
MutPred		0.51		.;Gain of relative solvent accessibility (P = 0.0522);.;
MVP		0.59
ClinPred		1.0	D
GERP RS		5.9
Varity_R		0.91
gMVP		0.77

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

Other links and lift over

dbSNP: rs747298393; hg19: chr1-33987086;