2-86785925-CG-C

Variant names:

• chr2-86785925-CG-C
• rs747233306
• NM_001768.7:c.702delC

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001768.7(CD8A):​c.702delC​(p.Tyr234fs) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000372 in 1,611,882 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: CD8A NM_001768.7 frameshift
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: -1.43

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CD8A	NM_001768.7	c.702delC	p.Tyr234fs	frameshift_variant	Exon 6 of 6	ENST00000283635.8	NP_001759.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CD8A	ENST00000283635.8	c.702delC	p.Tyr234fs	frameshift_variant	Exon 6 of 6	1	NM_001768.7	ENSP00000283635.3

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152202 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.000192

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

GnomAD3 exomes AF: 0.00000801 AC: 2 AN: 249666 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135102

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 SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000893

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1459562 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 726314

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000497

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152320 Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1 AN XY: 74474

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000756

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Susceptibility to respiratory infections associated with CD8alpha chain mutation Uncertain:2

May 10, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change creates a premature translational stop signal (p.Tyr234*) in the CD8A gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 2 amino acid(s) of the CD8A protein. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with CD8A-related conditions. ClinVar contains an entry for this variant (Variation ID: 626081). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Mar 30, 2021

Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

CD8A NM_001768.6 exon 6 p.Tyr234* (c.702delC): This variant has not been reported in the literature but is present in 1/109882 European alleles in the Genome Aggregation Database (http://gnomad.broadinstitute.org/rs747233306). Evolutionary conservation and computational predictive tools for this variant are limited or unavailable. This variant is a deletion of 1 nucleotide and creates a premature stop at this codon which is predicted to result in an absent or abnormal protein. However, there is insufficient evidence to establish loss of function as a disease mechanism for this gene. In addition, this variant occurs within the last exon of this gene; due to its position, it is possible that this protein may escape nonsense mediated decay. Further studies are needed to understand its impact. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain. -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs747233306; hg19: chr2-87013048;