2-86788530-C-G

Variant names:

• chr2-86788530-C-G
• rs138963205
• NM_001768.7:c.656G>C

Variant summary

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

The NM_001768.7(CD8A):​c.656G>C​(p.Arg219Pro) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000659 in 151,794 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. 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. R219W) has been classified as Uncertain significance.

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
• Consequence: CD8A NM_001768.7 missense, splice_region
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.31
• 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: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.

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.656G>C	p.Arg219Pro	missense splice_region	Exon 5 of 6	NP_001759.3
	CD8A	NM_001145873.1		c.656G>C	p.Arg219Pro	missense splice_region	Exon 8 of 9	NP_001139345.1	Q6ZVS2
	CD8A	NM_001382698.1		c.656G>C	p.Arg219Pro	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.656G>C	p.Arg219Pro	missense splice_region	Exon 5 of 6	ENSP00000283635.3	P01732-1
	CD8A	ENST00000409511.6	TSL:2	c.656G>C	p.Arg219Pro	missense splice_region	Exon 8 of 9	ENSP00000386559.2	P01732-1
	CD8A	ENST00000352580.7	TSL:2	c.545G>C	p.Arg182Pro	missense splice_region	Exon 4 of 5	ENSP00000321631.3	P01732-2

Frequencies

GnomAD3 genomes AF: 0.00000659 AC: 1 AN: 151794 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 31

GnomAD4 genome AF: 0.00000659 AC: 1 AN: 151794 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74090

African (AFR) AF: 0.0000242 AC: 1 AN: 41278

American (AMR) AF: 0.00 AC: 0 AN: 15254

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.00 AC: 0 AN: 4804

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10532

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67970

Other (OTH) AF: 0.00 AC: 0 AN: 2084

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.32
BayesDel_addAF	Pathogenic	0.23	D
BayesDel_noAF	Uncertain	0.090
CADD	Pathogenic	36
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.86	D
Eigen	Pathogenic	0.72
Eigen_PC	Uncertain	0.66
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Benign	0.74	T
M_CAP	Uncertain	0.16	D
MetaRNN	Pathogenic	0.81	D
MetaSVM	Uncertain	0.66	D
MutationAssessor	Pathogenic	3.0	M
PhyloP100		3.3
PrimateAI	Uncertain	0.62	T
PROVEAN	Uncertain	-4.0	D
REVEL	Uncertain	0.64
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.74
MutPred		0.57		Loss of MoRF binding (P = 3e-04)
MVP		0.96
MPC		1.8
ClinPred		1.0	D
GERP RS		5.0
Varity_R		0.91
gMVP		0.36
Mutation Taster		=54/46	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.98
SpliceAI score (max)		0.16		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: rs138963205; hg19: chr2-87015653;