1-33519633-T-C

Position:

• chr1-33519633-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_001281956.2(CSMD2):​c.10781A>G​(p.Asn3594Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: CSMD2 NM_001281956.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.64

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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.776

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CSMD2	NM_001281956.2	c.10781A>G	p.Asn3594Ser	missense_variant	70/71	ENST00000373381.9	NP_001268885.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CSMD2	ENST00000373381.9	c.10781A>G	p.Asn3594Ser	missense_variant	70/71	1	NM_001281956.2	ENSP00000362479.4
CSMD2	ENST00000373388.7	c.10349A>G	p.Asn3450Ser	missense_variant	69/70	1		ENSP00000362486.3
CSMD2	ENST00000619121.4	c.10661A>G	p.Asn3554Ser	missense_variant	70/71	5		ENSP00000483463.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 31

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

Aug 12, 2024

The c.10349A>G (p.N3450S) alteration is located in exon 69 (coding exon 69) of the CSMD2 gene. This alteration results from a A to G substitution at nucleotide position 10349, causing the asparagine (N) at amino acid position 3450 to be replaced by a serine (S). 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	Uncertain	0.38
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.44
CADD	Benign	20
DANN	Uncertain	1.0
DEOGEN2	Benign	0.18	.;T;T
Eigen	Uncertain	0.42
Eigen_PC	Uncertain	0.45
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.93	D;D;D
M_CAP	Benign	0.050	D
MetaRNN	Pathogenic	0.78	D;D;D
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	0.90	.;L;.
PrimateAI	Pathogenic	0.86	D
PROVEAN	Uncertain	-4.0	D;.;.
REVEL	Benign	0.25
Sift	Benign	0.080	T;.;.
Sift4G	Benign	0.074	T;T;T
Polyphen		0.88	.;P;.
Vest4		0.91
MutPred		0.37		.;Gain of catalytic residue at N3450 (P = 0.0811);.;
MVP		0.46
ClinPred		0.98	D
GERP RS		4.9
Varity_R		0.41
gMVP		0.57

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr1-33985233;