1-33519648-T-C

Variant names:

• chr1-33519648-T-C
• NM_001281956.2:c.10766A>G

Variant summary

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

The NM_001281956.2(CSMD2):​c.10766A>G​(p.Tyr3589Cys) variant causes a missense change. The variant allele was found at a frequency of 0.00000342 in 1,461,892 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: 31)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: CSMD2 NM_001281956.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.58

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 rank	MANE	Protein	UniProt
CSMD2	NM_001281956.2	c.10766A>G	p.Tyr3589Cys	missense_variant	Exon 70 of 71	ENST00000373381.9	NP_001268885.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CSMD2	ENST00000373381.9	c.10766A>G	p.Tyr3589Cys	missense_variant	Exon 70 of 71	1	NM_001281956.2	ENSP00000362479.4
CSMD2	ENST00000373388.7	c.10334A>G	p.Tyr3445Cys	missense_variant	Exon 69 of 70	1		ENSP00000362486.3
CSMD2	ENST00000619121.4	c.10646A>G	p.Tyr3549Cys	missense_variant	Exon 70 of 71	5		ENSP00000483463.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000342 AC: 5 AN: 1461892 Hom.: 0 Cov.: 33 AF XY: 0.00000275 AC XY: 2 AN XY: 727248

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: 0.00000360

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 31

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Nov 11, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.10334A>G (p.Y3445C) 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 10334, causing the tyrosine (Y) at amino acid position 3445 to be replaced by a cysteine (C). 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	0.76
BayesDel_addAF	Benign	-0.0092	T
BayesDel_noAF	Benign	-0.25
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.021	.;T;T
Eigen	Uncertain	0.38
Eigen_PC	Uncertain	0.38
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.95	D;D;D
M_CAP	Benign	0.031	D
MetaRNN	Pathogenic	0.78	D;D;D
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.3	.;L;.
PrimateAI	Pathogenic	0.90	D
PROVEAN	Benign	-1.4	N;.;.
REVEL	Benign	0.16
Sift	Benign	0.14	T;.;.
Sift4G	Benign	0.13	T;T;T
Polyphen		0.87	.;P;.
Vest4		0.85
MutPred		0.59		.;Loss of phosphorylation at Y3445 (P = 0.0344);.;
MVP		0.44
ClinPred		0.89	D
GERP RS		4.9
Varity_R		0.29
gMVP		0.53

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr1-33985248;