2-86790539-G-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001768.7(CD8A):c.192C>A(p.Ala64=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0713 in 1,613,474 control chromosomes in the GnomAD database, including 4,531 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. A64A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.070 (407 hom., cov: 33)
  • Exomes 𝑓: 0.071 (4124 hom.)
• Consequence: CD8A NM_001768.7 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.0350

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.71).
• BP6: Variant 2-86790539-G-T is Benign according to our data. Variant chr2-86790539-G-T is described in ClinVar as [Benign]. Clinvar id is 402523.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.035 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0808 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CD8A	NM_001768.7	c.192C>A	p.Ala64=	synonymous_variant	2/6	ENST00000283635.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CD8A	ENST00000283635.8	c.192C>A	p.Ala64=	synonymous_variant	2/6	1	NM_001768.7	P1

Frequencies

GnomAD3 genomes AF: 0.0698 AC: 10612 AN: 152118 Hom.: 407 Cov.: 33

Gnomad AFR AF: 0.0830

Gnomad AMI AF: 0.0877

Gnomad AMR AF: 0.0470

Gnomad ASJ AF: 0.0542

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0128

Gnomad FIN AF: 0.0580

Gnomad MID AF: 0.0669

Gnomad NFE AF: 0.0787

Gnomad OTH AF: 0.0675

GnomAD3 exomes AF: 0.0574 AC: 14110 AN: 245704 Hom.: 523 AF XY: 0.0562 AC XY: 7527 AN XY: 133994

Gnomad AFR exome AF: 0.0831

Gnomad AMR exome AF: 0.0343

Gnomad ASJ exome AF: 0.0584

Gnomad EAS exome AF: 0.000165

Gnomad SAS exome AF: 0.0190

Gnomad FIN exome AF: 0.0591

Gnomad NFE exome AF: 0.0810

Gnomad OTH exome AF: 0.0568

GnomAD4 exome AF: 0.0715 AC: 104406 AN: 1461238 Hom.: 4124 Cov.: 34 AF XY: 0.0699 AC XY: 50834 AN XY: 726956

Gnomad4 AFR exome AF: 0.0830

Gnomad4 AMR exome AF: 0.0360

Gnomad4 ASJ exome AF: 0.0561

Gnomad4 EAS exome AF: 0.000151

Gnomad4 SAS exome AF: 0.0197

Gnomad4 FIN exome AF: 0.0589

Gnomad4 NFE exome AF: 0.0805

Gnomad4 OTH exome AF: 0.0637

GnomAD4 genome AF: 0.0698 AC: 10623 AN: 152236 Hom.: 407 Cov.: 33 AF XY: 0.0672 AC XY: 5000 AN XY: 74434

Gnomad4 AFR AF: 0.0831

Gnomad4 AMR AF: 0.0469

Gnomad4 ASJ AF: 0.0542

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.0124

Gnomad4 FIN AF: 0.0580

Gnomad4 NFE AF: 0.0787

Gnomad4 OTH AF: 0.0668

Alfa AF: 0.0592 Hom.: 144

Bravo AF: 0.0689

Asia WGS AF: 0.0130 AC: 44 AN: 3478

EpiCase AF: 0.0767

EpiControl AF: 0.0801

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Mar 28, 2016

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: MAF -

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

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.71
Cadd	Benign	5.0
Dann	Benign	0.60

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: rs2229239; hg19: chr2-87017662; COSMIC: COSV52156416;