chr2-86789760-C-G

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_001768.7(CD8A):​c.404-10G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000857 in 1,347,110 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.00049 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00090 (2 hom.)
• Consequence: CD8A NM_001768.7 intron
• Scores: Splicing: ADA: 0.0001094
• 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: Benign. The variant received -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BP6: Variant 2-86789760-C-G is Benign according to our data. Variant chr2-86789760-C-G is described in ClinVar as Likely_benign. ClinVar VariationId is 464447.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Homozygotes in GnomAdExome4 at 2 AR gene

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>C		intron	N/A	NP_001759.3
	CD8A	NM_001145873.1		c.404-10G>C		intron	N/A	NP_001139345.1
	CD8A	NM_001382698.1		c.404-10G>C		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>C		intron	N/A	ENSP00000283635.3
	CD8A	ENST00000409511.6	TSL:2	c.404-10G>C		intron	N/A	ENSP00000386559.2
	CD8A	ENST00000352580.7	TSL:2	c.404-10G>C		intron	N/A	ENSP00000321631.3

Frequencies

GnomAD3 genomes AF: 0.000493 AC: 75 AN: 152140 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000966

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000283

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00100

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000462 AC: 9 AN: 19464 AF XY: 0.000295

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: 0.000749

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000903 AC: 1079 AN: 1194858 Hom.: 2 Cov.: 26 AF XY: 0.000830 AC XY: 479 AN XY: 576856

African (AFR) AF: 0.000209 AC: 5 AN: 23884

American (AMR) AF: 0.0000842 AC: 1 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: 0.0000225 AC: 1 AN: 44534

European-Finnish (FIN) AF: 0.000855 AC: 24 AN: 28062

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

European-Non Finnish (NFE) AF: 0.00104 AC: 1022 AN: 987106

Other (OTH) AF: 0.000526 AC: 26 AN: 49394

GnomAD4 genome AF: 0.000493 AC: 75 AN: 152252 Hom.: 0 Cov.: 33 AF XY: 0.000416 AC XY: 31 AN XY: 74452

African (AFR) AF: 0.0000963 AC: 4 AN: 41532

American (AMR) AF: 0.00 AC: 0 AN: 15304

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5166

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.000283 AC: 3 AN: 10616

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.00100 AC: 68 AN: 68018

Other (OTH) AF: 0.00 AC: 0 AN: 2116

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.000502

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	-0.79
CADD	Benign	12
DANN	Benign	0.62
PhyloP100		0.54
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00011
dbscSNV1_RF	Benign	0.0020
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: rs746824602; hg19: chr2-87016883;