2-86789760-C-A

Variant names:

• chr2-86789760-C-A
• rs746824602
• NM_001768.7:c.404-10G>T

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 2P and 6B. PM2 BP4_Strong BP6_Moderate

The NM_001768.7(CD8A):​c.404-10G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000141 in 1,347,002 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000013 (0 hom.)
• Consequence: CD8A NM_001768.7 intron
• Scores: Splicing: ADA: 0.00009522
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.541
• Publications: 0 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: Ambry Genetics, Labcorp Genetics (formerly Invitae), Orphanet, ClinGen

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.78).
• BP6: Variant 2-86789760-C-A is Benign according to our data. Variant chr2-86789760-C-A is described in ClinVar as Likely_benign. ClinVar VariationId is 2059156.Status of the report is criteria_provided_single_submitter, 1 stars.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CD8A	NM_001768.7	MANE Select	c.404-10G>T		intron	N/A	NP_001759.3
	CD8A	NM_001145873.1		c.404-10G>T		intron	N/A	NP_001139345.1
	CD8A	NM_001382698.1		c.404-10G>T		intron	N/A	NP_001369627.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CD8A	ENST00000283635.8	TSL:1 MANE Select	c.404-10G>T		intron	N/A	ENSP00000283635.3
	CD8A	ENST00000409511.6	TSL:2	c.404-10G>T		intron	N/A	ENSP00000386559.2
	CD8A	ENST00000352580.7	TSL:2	c.404-10G>T		intron	N/A	ENSP00000321631.3

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152140 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

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

GnomAD2 exomes AF: 0.0000514 AC: 1 AN: 19464 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000491

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000134 AC: 16 AN: 1194862 Hom.: 0 Cov.: 26 AF XY: 0.0000104 AC XY: 6 AN XY: 576858

African (AFR) AF: 0.00 AC: 0 AN: 23884

American (AMR) AF: 0.000252 AC: 3 AN: 11882

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 16574

East Asian (EAS) AF: 0.00 AC: 0 AN: 28460

South Asian (SAS) AF: 0.00 AC: 0 AN: 44534

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 28062

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4962

European-Non Finnish (NFE) AF: 0.0000132 AC: 13 AN: 987110

Other (OTH) AF: 0.00 AC: 0 AN: 49394

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152140 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 74330

African (AFR) AF: 0.0000483 AC: 2 AN: 41412

American (AMR) AF: 0.0000654 AC: 1 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68026

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000227

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	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	-0.78
CADD	Benign	12
DANN	Benign	0.73
PhyloP100		0.54

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000095
dbscSNV1_RF	Benign	0.0060
SpliceAI score (max)		0.040		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: rs746824602; hg19: chr2-87016883;