rs3020726

Variant names:

• chr2-86789383-A-G
• rs3020726
• NM_001768.7:c.565T>C

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.565T>C​(p.Leu189Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.141 in 1,613,118 control chromosomes in the GnomAD database, including 17,203 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.12 (1223 hom., cov: 33)
  • Exomes 𝑓: 0.14 (15980 hom.)
• Consequence: CD8A NM_001768.7 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.163
• Publications: 12 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=-0.79).
• BP6: Variant 2-86789383-A-G is Benign according to our data. Variant chr2-86789383-A-G is described in ClinVar as Benign. ClinVar VariationId is 402521.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.163 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.16 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.565T>C	p.Leu189Leu	synonymous	Exon 4 of 6	NP_001759.3
	CD8A	NM_001145873.1		c.565T>C	p.Leu189Leu	synonymous	Exon 7 of 9	NP_001139345.1	Q6ZVS2
	CD8A	NM_001382698.1		c.565T>C	p.Leu189Leu	synonymous	Exon 6 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.565T>C	p.Leu189Leu	synonymous	Exon 4 of 6	ENSP00000283635.3	P01732-1
	CD8A	ENST00000409511.6	TSL:2	c.565T>C	p.Leu189Leu	synonymous	Exon 7 of 9	ENSP00000386559.2	P01732-1
	CD8A	ENST00000409781.1	TSL:5	c.454T>C	p.Leu152Leu	synonymous	Exon 3 of 5	ENSP00000387314.1	B8ZZZ4

Frequencies

GnomAD3 genomes AF: 0.119 AC: 18132 AN: 152042 Hom.: 1223 Cov.: 33

Gnomad AFR AF: 0.0846

Gnomad AMI AF: 0.179

Gnomad AMR AF: 0.0826

Gnomad ASJ AF: 0.126

Gnomad EAS AF: 0.0692

Gnomad SAS AF: 0.0483

Gnomad FIN AF: 0.0798

Gnomad MID AF: 0.149

Gnomad NFE AF: 0.163

Gnomad OTH AF: 0.113

GnomAD2 exomes AF: 0.115 AC: 28955 AN: 251446 AF XY: 0.115

Gnomad AFR exome AF: 0.0811

Gnomad AMR exome AF: 0.0690

Gnomad ASJ exome AF: 0.113

Gnomad EAS exome AF: 0.0714

Gnomad FIN exome AF: 0.0881

Gnomad NFE exome AF: 0.163

Gnomad OTH exome AF: 0.119

GnomAD4 exome AF: 0.143 AC: 208915 AN: 1460958 Hom.: 15980 Cov.: 31 AF XY: 0.141 AC XY: 102303 AN XY: 726810

African (AFR) AF: 0.0839 AC: 2809 AN: 33472

American (AMR) AF: 0.0719 AC: 3215 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.118 AC: 3085 AN: 26124

East Asian (EAS) AF: 0.0598 AC: 2375 AN: 39698

South Asian (SAS) AF: 0.0562 AC: 4851 AN: 86244

European-Finnish (FIN) AF: 0.0914 AC: 4883 AN: 53418

Middle Eastern (MID) AF: 0.140 AC: 806 AN: 5768

European-Non Finnish (NFE) AF: 0.161 AC: 179328 AN: 1111154

Other (OTH) AF: 0.125 AC: 7563 AN: 60356

GnomAD4 genome AF: 0.119 AC: 18136 AN: 152160 Hom.: 1223 Cov.: 33 AF XY: 0.113 AC XY: 8415 AN XY: 74388

African (AFR) AF: 0.0845 AC: 3510 AN: 41538

American (AMR) AF: 0.0825 AC: 1263 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.126 AC: 436 AN: 3472

East Asian (EAS) AF: 0.0692 AC: 355 AN: 5132

South Asian (SAS) AF: 0.0494 AC: 238 AN: 4818

European-Finnish (FIN) AF: 0.0798 AC: 847 AN: 10608

Middle Eastern (MID) AF: 0.153 AC: 45 AN: 294

European-Non Finnish (NFE) AF: 0.162 AC: 11043 AN: 67972

Other (OTH) AF: 0.112 AC: 236 AN: 2114

Alfa AF: 0.147 Hom.: 858

Bravo AF: 0.119

Asia WGS AF: 0.0630 AC: 219 AN: 3478

EpiCase AF: 0.164

EpiControl AF: 0.154

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not specified (2)
-	-	1	not provided (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	-0.79
CADD	Benign	9.5
DANN	Benign	0.42
PhyloP100		0.16
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs3020726; hg19: chr2-87016506; COSMIC: COSV52157627;