1-33519675-C-T

Variant names:

• chr1-33519675-C-T
• rs151161296
• NM_001281956.2:c.10739G>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001281956.2(CSMD2):​c.10739G>A​(p.Arg3580Lys) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. 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. R3580T) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 31)
• Consequence: CSMD2 NM_001281956.2 missense, splice_region
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.94
• Publications: 0 publications found

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

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.18018329).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001281956.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CSMD2	NM_001281956.2	MANE Select	c.10739G>A	p.Arg3580Lys	missense splice_region	Exon 70 of 71	NP_001268885.1	Q7Z408-4
	CSMD2	NM_052896.5		c.10307G>A	p.Arg3436Lys	missense splice_region	Exon 69 of 70	NP_443128.2	Q7Z408-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CSMD2	ENST00000373381.9	TSL:1 MANE Select	c.10739G>A	p.Arg3580Lys	missense splice_region	Exon 70 of 71	ENSP00000362479.4	Q7Z408-4
	CSMD2	ENST00000373388.7	TSL:1	c.10307G>A	p.Arg3436Lys	missense splice_region	Exon 69 of 70	ENSP00000362486.3	Q7Z408-1
	CSMD2	ENST00000619121.4	TSL:5	c.10619G>A	p.Arg3540Lys	missense splice_region	Exon 70 of 71	ENSP00000483463.1	A0A087X0K4

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251256 AF XY: 0.00000736

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: 0.00000881

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.48
CADD	Benign	22
DANN	Benign	0.89
DEOGEN2	Benign	0.016	T
Eigen	Benign	-0.17
Eigen_PC	Benign	0.034
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.73	T
M_CAP	Benign	0.0087	T
MetaRNN	Benign	0.18	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.84	L
PhyloP100		2.9
PrimateAI	Pathogenic	0.92	D
PROVEAN	Benign	-0.75	N
REVEL	Benign	0.048
Sift	Benign	0.88	T
Sift4G	Benign	0.96	T
Polyphen		0.017	B
Vest4		0.31
MutPred		0.37		Gain of methylation at R3436 (P = 0.0173)
MVP		0.37
ClinPred		0.34	T
GERP RS		4.9
Varity_R		0.35
gMVP		0.29
Mutation Taster		=81/19	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs151161296; hg19: chr1-33985275;