chr15-73702541-C-G

Position:

• chr15-73702541-C-G

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_001024736.2(CD276):​c.366C>G​(p.Cys122Trp) variant causes a missense change involving the alteration of a non-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: 33)
• Consequence: CD276 NM_001024736.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.53

Genes affected

CD276 (HGNC:19137): (CD276 molecule) The protein encoded by this gene belongs to the immunoglobulin superfamily, and thought to participate in the regulation of T-cell-mediated immune response. Studies show that while the transcript of this gene is ubiquitously expressed in normal tissues and solid tumors, the protein is preferentially expressed only in tumor tissues. Additionally, it was observed that the 3' UTR of this transcript contains a target site for miR29 microRNA, and there is an inverse correlation between the expression of this protein and miR29 levels, suggesting regulation of expression of this gene product by miR29. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Sep 2011]

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.974

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CD276	NM_001024736.2	c.366C>G	p.Cys122Trp	missense_variant	3/10	ENST00000318443.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CD276	ENST00000318443.10	c.366C>G	p.Cys122Trp	missense_variant	3/10	2	NM_001024736.2	P2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 33

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

Feb 28, 2024

The c.366C>G (p.C122W) alteration is located in exon 3 (coding exon 2) of the CD276 gene. This alteration results from a C to G substitution at nucleotide position 366, causing the cysteine (C) at amino acid position 122 to be replaced by a tryptophan (W). 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	0.98
BayesDel_addAF	Pathogenic	0.27	D
BayesDel_noAF	Pathogenic	0.15
CADD	Pathogenic	27
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.50	T;D;.;T;.;.;T;T;.
Eigen	Uncertain	0.43
Eigen_PC	Uncertain	0.24
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.93	.;D;D;D;D;D;D;D;.
M_CAP	Uncertain	0.17	D
MetaRNN	Pathogenic	0.97	D;D;D;D;D;D;D;D;D
MetaSVM	Benign	-0.66	T
MutationAssessor	Pathogenic	4.3	.;H;H;.;.;H;.;.;H
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Pathogenic	0.90	D
PROVEAN	Pathogenic	-10	D;D;D;D;D;D;D;D;D
REVEL	Uncertain	0.57
Sift	Pathogenic	0.0	D;D;D;D;D;D;D;D;D
Sift4G	Pathogenic	0.0	D;D;D;D;D;D;D;D;D
Polyphen		1.0	.;D;D;.;.;D;.;.;D
Vest4		0.97, 0.92, 0.97
MutPred		0.88		Loss of stability (P = 0.0635);Loss of stability (P = 0.0635);Loss of stability (P = 0.0635);Loss of stability (P = 0.0635);Loss of stability (P = 0.0635);Loss of stability (P = 0.0635);Loss of stability (P = 0.0635);Loss of stability (P = 0.0635);Loss of stability (P = 0.0635);
MVP		0.67
MPC		0.71
ClinPred		1.0	D
GERP RS		1.9
Varity_R		0.84
gMVP		0.77

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		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: chr15-73994882;