rs147048705

Positions:

• chr2-86790578-C-A
• chr2-86790578-C-T

Variant summary

Our verdict is Benign. Variant got -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BP7 BS2

The NM_001768.7(CD8A):​c.153G>T​(p.Thr51=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00513 in 1,612,602 control chromosomes in the GnomAD database, including 30 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0030 (2 hom., cov: 33)
  • Exomes 𝑓: 0.0053 (28 hom.)
• Consequence: CD8A NM_001768.7 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -3.22

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 Benign. Variant got -17 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.58).
• BP6: Variant 2-86790578-C-A is Benign according to our data. Variant chr2-86790578-C-A is described in ClinVar as [Likely_benign]. Clinvar id is 464445.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-86790578-C-A is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-3.22 with no splicing effect.
• BS2: High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CD8A	NM_001768.7	c.153G>T	p.Thr51=	synonymous_variant	2/6	ENST00000283635.8	NP_001759.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CD8A	ENST00000283635.8	c.153G>T	p.Thr51=	synonymous_variant	2/6	1	NM_001768.7	ENSP00000283635	P1

Frequencies

GnomAD3 genomes AF: 0.00306 AC: 466 AN: 152178 Hom.: 2 Cov.: 33

Gnomad AFR AF: 0.00128

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00183

Gnomad ASJ AF: 0.000866

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.000754

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00541

Gnomad OTH AF: 0.000956

GnomAD3 exomes AF: 0.00310 AC: 759 AN: 244788 Hom.: 4 AF XY: 0.00312 AC XY: 416 AN XY: 133346

Gnomad AFR exome AF: 0.000835

Gnomad AMR exome AF: 0.000638

Gnomad ASJ exome AF: 0.000703

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000950

Gnomad FIN exome AF: 0.00162

Gnomad NFE exome AF: 0.00582

Gnomad OTH exome AF: 0.00314

GnomAD4 exome AF: 0.00534 AC: 7802 AN: 1460306 Hom.: 28 Cov.: 34 AF XY: 0.00524 AC XY: 3809 AN XY: 726522

Gnomad4 AFR exome AF: 0.00102

Gnomad4 AMR exome AF: 0.000514

Gnomad4 ASJ exome AF: 0.000498

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00114

Gnomad4 FIN exome AF: 0.00156

Gnomad4 NFE exome AF: 0.00657

Gnomad4 OTH exome AF: 0.00399

GnomAD4 genome AF: 0.00305 AC: 464 AN: 152296 Hom.: 2 Cov.: 33 AF XY: 0.00279 AC XY: 208 AN XY: 74474

Gnomad4 AFR AF: 0.00127

Gnomad4 AMR AF: 0.00183

Gnomad4 ASJ AF: 0.000866

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.000622

Gnomad4 FIN AF: 0.000754

Gnomad4 NFE AF: 0.00538

Gnomad4 OTH AF: 0.000946

Alfa AF: 0.00418 Hom.: 0

Bravo AF: 0.00300

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00403

EpiControl AF: 0.00545

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Dec 01, 2023	CD8A: BP4, BP7, BS2 -

Susceptibility to respiratory infections associated with CD8alpha chain mutation Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

- -

CD8A-related disorder Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 03, 2019

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.58
CADD	Benign	0.80
DANN	Benign	0.65

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: rs147048705; hg19: chr2-87017701;