2-86790539-G-T

Variant names:

• chr2-86790539-G-T
• rs2229239
• NM_001768.7:c.192C>A

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001768.7(CD8A):​c.192C>A​(p.Ala64Ala) 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:3
• Conservation: PhyloP100: -0.0350
• 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: Benign. The variant received -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 VariationId 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.

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.192C>A	p.Ala64Ala	synonymous	Exon 2 of 6	NP_001759.3
	CD8A	NM_001145873.1		c.192C>A	p.Ala64Ala	synonymous	Exon 5 of 9	NP_001139345.1	Q6ZVS2
	CD8A	NM_001382698.1		c.192C>A	p.Ala64Ala	synonymous	Exon 4 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.192C>A	p.Ala64Ala	synonymous	Exon 2 of 6	ENSP00000283635.3	P01732-1
	CD8A	ENST00000409511.6	TSL:2	c.192C>A	p.Ala64Ala	synonymous	Exon 5 of 9	ENSP00000386559.2	P01732-1
	CD8A	ENST00000352580.7	TSL:2	c.192C>A	p.Ala64Ala	synonymous	Exon 2 of 5	ENSP00000321631.3	P01732-2

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

GnomAD2 exomes AF: 0.0574 AC: 14110 AN: 245704 AF XY: 0.0562

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 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

African (AFR) AF: 0.0830 AC: 2780 AN: 33476

American (AMR) AF: 0.0360 AC: 1609 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.0561 AC: 1467 AN: 26128

East Asian (EAS) AF: 0.000151 AC: 6 AN: 39700

South Asian (SAS) AF: 0.0197 AC: 1701 AN: 86256

European-Finnish (FIN) AF: 0.0589 AC: 3114 AN: 52910

Middle Eastern (MID) AF: 0.0605 AC: 349 AN: 5766

European-Non Finnish (NFE) AF: 0.0805 AC: 89536 AN: 1111902

Other (OTH) AF: 0.0637 AC: 3844 AN: 60378

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

African (AFR) AF: 0.0831 AC: 3454 AN: 41548

American (AMR) AF: 0.0469 AC: 718 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.0542 AC: 188 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5162

South Asian (SAS) AF: 0.0124 AC: 60 AN: 4830

European-Finnish (FIN) AF: 0.0580 AC: 616 AN: 10616

Middle Eastern (MID) AF: 0.0582 AC: 17 AN: 292

European-Non Finnish (NFE) AF: 0.0787 AC: 5349 AN: 67994

Other (OTH) AF: 0.0668 AC: 141 AN: 2112

Alfa AF: 0.0593 Hom.: 148

Bravo AF: 0.0689

Asia WGS AF: 0.0130 AC: 44 AN: 3478

EpiCase AF: 0.0767

EpiControl AF: 0.0801

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)
-	-	1	not specified (1)
-	-	1	Susceptibility to respiratory infections associated with CD8alpha chain mutation (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.71
CADD	Benign	5.0
DANN	Benign	0.60
PhyloP100		-0.035
PromoterAI		-0.0024	Neutral
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

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