rs770405273

Variant names:

• chr2-86788531-G-A
• rs770405273
• NM_001768.7:c.655C>T

Your query was ambiguous. Multiple possible variants found:

• chr2-86788531-G-A
• chr2-86788531-G-C

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_001768.7(CD8A):​c.655C>T​(p.Arg219Trp) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000411 in 1,460,616 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. 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. R219G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: CD8A NM_001768.7 missense, splice_region
• Scores: Splicing: ADA: 0.001145
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.734
• Publications: 5 publications found

Genes affected

CD8A (HGNC:1706): (CD8 subunit alpha) 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 acts as a coreceptor with the T-cell receptor on the T lymphocyte to recognize antigens displayed by an antigen presenting cell in the context of class I MHC molecules. The coreceptor functions as either a homodimer composed of two alpha chains or as 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 alpha chain. Multiple transcript variants encoding different isoforms have been found for this gene. The major protein isoforms of this gene differ by the presence or absence of a transmembrane domain and thus differ in being a membrane-anchored or secreted protein. [provided by RefSeq, May 2020]

CD8A Gene-Disease associations (from GenCC):

• susceptibility to respiratory infections associated with CD8alpha chain mutation

  Inheritance: AR Classification: STRONG, SUPPORTIVE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, ClinGen, Ambry Genetics

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.794

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001768.7. 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
	CD8A	NM_001768.7	MANE Select	c.655C>T	p.Arg219Trp	missense splice_region	Exon 5 of 6	NP_001759.3
	CD8A	NM_001145873.1		c.655C>T	p.Arg219Trp	missense splice_region	Exon 8 of 9	NP_001139345.1	Q6ZVS2
	CD8A	NM_001382698.1		c.655C>T	p.Arg219Trp	missense splice_region	Exon 7 of 8	NP_001369627.1	P01732-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CD8A	ENST00000283635.8	TSL:1 MANE Select	c.655C>T	p.Arg219Trp	missense splice_region	Exon 5 of 6	ENSP00000283635.3	P01732-1
	CD8A	ENST00000409511.6	TSL:2	c.655C>T	p.Arg219Trp	missense splice_region	Exon 8 of 9	ENSP00000386559.2	P01732-1
	CD8A	ENST00000352580.7	TSL:2	c.544C>T	p.Arg182Trp	missense splice_region	Exon 4 of 5	ENSP00000321631.3	P01732-2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000120 AC: 3 AN: 250564 AF XY: 0.0000222

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: 0.0000463

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000411 AC: 6 AN: 1460616 Hom.: 0 Cov.: 31 AF XY: 0.00000688 AC XY: 5 AN XY: 726566

African (AFR) AF: 0.0000299 AC: 1 AN: 33442

American (AMR) AF: 0.00 AC: 0 AN: 44674

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26122

East Asian (EAS) AF: 0.00 AC: 0 AN: 39694

South Asian (SAS) AF: 0.0000349 AC: 3 AN: 86012

European-Finnish (FIN) AF: 0.0000187 AC: 1 AN: 53410

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111134

Other (OTH) AF: 0.0000166 AC: 1 AN: 60360

GnomAD4 genome Cov.: 32

ExAC AF: 0.0000165 AC: 2

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Susceptibility to respiratory infections associated with CD8alpha chain mutation (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.31
BayesDel_addAF	Benign	0.0019	T
BayesDel_noAF	Uncertain	-0.050
CADD	Uncertain	26
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.86	D
Eigen	Benign	0.016
Eigen_PC	Benign	-0.064
FATHMM_MKL	Benign	0.51	D
LIST_S2	Uncertain	0.86	D
M_CAP	Pathogenic	0.33	D
MetaRNN	Pathogenic	0.79	D
MetaSVM	Uncertain	0.53	D
MutationAssessor	Pathogenic	3.0	M
PhyloP100		0.73
PrimateAI	Uncertain	0.67	T
PROVEAN	Pathogenic	-4.8	D
REVEL	Pathogenic	0.65
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.72
MutPred		0.57		Loss of disorder (P = 0.0034)
MVP		0.95
MPC		1.5
ClinPred		0.96	D
GERP RS		2.5
Varity_R		0.63
gMVP		0.36
Mutation Taster		=86/14	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0011
dbscSNV1_RF	Benign	0.14
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: rs770405273; hg19: chr2-87015654; COSMIC: COSV52159672;