2-86858080-C-A

Variant names:

• chr2-86858080-C-A
• NM_004931.5:c.380G>T

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_004931.5(CD8B):​c.380G>T​(p.Gly127Val) 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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G127R) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 31)
• Consequence: CD8B NM_004931.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.44

Genes affected

CD8B (HGNC:1707): (CD8 subunit beta) The CD8 antigen is a cell surface glycoprotein found on most cytotoxic T lymphocytes that mediates efficient cell-cell interactions within the immune system. The CD8 antigen, acting as a coreceptor, and the T-cell receptor on the T lymphocyte recognize antigens displayed by an antigen presenting cell (APC) in the context of class I MHC molecules. The functional coreceptor is either a homodimer composed of two alpha chains, or a heterodimer composed of one alpha and one beta chain. Both alpha and beta chains share significant homology to immunoglobulin variable light chains. This gene encodes the CD8 beta chain isoforms. Multiple alternatively spliced transcript variants encoding distinct membrane associated or secreted isoforms have been described. A pseudogene, also located on chromosome 2, has been identified. [provided by RefSeq, May 2010]

ENSG00000291013 (HGNC:):

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.988

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CD8B	NM_004931.5	c.380G>T	p.Gly127Val	missense_variant	Exon 2 of 6	ENST00000390655.12	NP_004922.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CD8B	ENST00000390655.12	c.380G>T	p.Gly127Val	missense_variant	Exon 2 of 6	1	NM_004931.5	ENSP00000375070.6

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 37

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Sep 17, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.380G>T (p.G127V) alteration is located in exon 2 (coding exon 2) of the CD8B gene. This alteration results from a G to T substitution at nucleotide position 380, causing the glycine (G) at amino acid position 127 to be replaced by a valine (V). 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	0.88
BayesDel_addAF	Pathogenic	0.35	D
BayesDel_noAF	Pathogenic	0.27
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.51	.;.;.;.;D;T
Eigen	Uncertain	0.50
Eigen_PC	Uncertain	0.33
FATHMM_MKL	Benign	0.76	D
LIST_S2	Benign	0.78	T;T;T;T;T;T
M_CAP	Uncertain	0.12	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D;D
MetaSVM	Uncertain	0.35	D
PhyloP100		3.4
PrimateAI	Benign	0.38	T
PROVEAN	Pathogenic	-8.6	D;D;D;D;D;.
REVEL	Pathogenic	0.73
Sift	Pathogenic	0.0	D;D;D;D;D;.
Sift4G	Pathogenic	0.0	D;D;D;D;D;D
Polyphen		1.0	.;D;D;D;D;.
Vest4		0.75
MutPred		0.92		Gain of catalytic residue at G127 (P = 0.0291);Gain of catalytic residue at G127 (P = 0.0291);Gain of catalytic residue at G127 (P = 0.0291);Gain of catalytic residue at G127 (P = 0.0291);Gain of catalytic residue at G127 (P = 0.0291);Gain of catalytic residue at G127 (P = 0.0291);
MVP		0.91
MPC		1.7
ClinPred		0.99	D
GERP RS		4.5
Varity_R		0.80
gMVP		0.80
Mutation Taster		=44/56	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		Details are displayed if max score is > 0.2

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

Publications

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Other links and lift over

hg19: chr2-87085203;