1-33527252-C-A

Variant names:

• chr1-33527252-C-A
• rs148437366
• NM_001281956.2:c.10178G>T

Variant summary

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

The NM_001281956.2(CSMD2):​c.10178G>T​(p.Arg3393Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,460,566 control chromosomes in the GnomAD database, with no homozygous occurrence. 13/22 in silico tools predict a benign outcome for this variant. 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. R3393Q) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: CSMD2 NM_001281956.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.38
• Publications: 1 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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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.10178G>T	p.Arg3393Leu	missense	Exon 65 of 71	NP_001268885.1	Q7Z408-4
	CSMD2	NM_052896.5		c.9746G>T	p.Arg3249Leu	missense	Exon 64 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.10178G>T	p.Arg3393Leu	missense	Exon 65 of 71	ENSP00000362479.4	Q7Z408-4
	CSMD2	ENST00000373388.7	TSL:1	c.9746G>T	p.Arg3249Leu	missense	Exon 64 of 70	ENSP00000362486.3	Q7Z408-1
	CSMD2	ENST00000619121.4	TSL:5	c.10058G>T	p.Arg3353Leu	missense	Exon 65 of 71	ENSP00000483463.1	A0A087X0K4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000401 AC: 1 AN: 249642 AF XY: 0.00

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: 0.00000887

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460566 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 726500

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33414

American (AMR) AF: 0.00 AC: 0 AN: 44508

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26098

East Asian (EAS) AF: 0.00 AC: 0 AN: 39666

South Asian (SAS) AF: 0.00 AC: 0 AN: 85994

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53406

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5760

European-Non Finnish (NFE) AF: 9.00e-7 AC: 1 AN: 1111384

Other (OTH) AF: 0.00 AC: 0 AN: 60336

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Benign	-0.017	T
BayesDel_noAF	Benign	-0.26
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.024	T
Eigen	Benign	0.032
Eigen_PC	Benign	0.21
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.82	T
M_CAP	Benign	0.0062	T
MetaRNN	Uncertain	0.46	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.2	L
PhyloP100		3.4
PrimateAI	Uncertain	0.65	T
PROVEAN	Benign	-1.7	N
REVEL	Benign	0.15
Sift	Benign	0.15	T
Sift4G	Benign	0.28	T
Polyphen		0.0	B
Vest4		0.76
MutPred		0.56		Loss of disorder (P = 0.038)
MVP		0.35
ClinPred		0.76	D
GERP RS		5.4
Varity_R		0.20
gMVP		0.61
Mutation Taster		=42/58	disease causing

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

Other links and lift over

dbSNP: rs148437366; hg19: chr1-33992852;