Genetic Variant CD8A:p.Ala135Ala (chr2-86789749-C-A) – ACMG Classification: Likely_benign (-3 pts)

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PM2BP4_StrongBP7

The NM_001768.7(CD8A):c.405G>T(p.Ala135Ala) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. A135A) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

CD8A
NM_001768.7 splice_region, synonymous

Scores

Splicing: ADA: 0.00003707

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -3.26

Publications

0 publications found

Variant links:

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

CD8A links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.69).

BP7

Synonymous conserved (PhyloP=-3.26 with no splicing effect.

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CD8A	NM_001768.7	MANE Select	c.405G>T	p.Ala135Ala	splice_region synonymous	Exon 3 of 6	NP_001759.3
CD8A	NM_001145873.1		c.405G>T	p.Ala135Ala	splice_region synonymous	Exon 6 of 9	NP_001139345.1	Q6ZVS2
CD8A	NM_001382698.1		c.405G>T	p.Ala135Ala	splice_region synonymous	Exon 5 of 8	NP_001369627.1	P01732-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CD8A	ENST00000283635.8	TSL:1 MANE Select	c.405G>T	p.Ala135Ala	splice_region synonymous	Exon 3 of 6	ENSP00000283635.3	P01732-1
CD8A	ENST00000409511.6	TSL:2	c.405G>T	p.Ala135Ala	splice_region synonymous	Exon 6 of 9	ENSP00000386559.2	P01732-1
CD8A	ENST00000352580.7	TSL:2	c.405G>T	p.Ala135Ala	splice_region synonymous	Exon 3 of 5	ENSP00000321631.3	P01732-2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.0000395

AC:

AN:

25290

AF XY:

0.0000737

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

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

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1204452

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

582844

African (AFR)

AF:

0.00

AC:

AN:

24196

American (AMR)

AF:

0.00

AC:

AN:

12474

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

16870

East Asian (EAS)

AF:

0.00

AC:

AN:

28626

South Asian (SAS)

AF:

0.00

AC:

AN:

45214

European-Finnish (FIN)

AF:

0.00

AC:

AN:

28414

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4980

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

993956

Other (OTH)

AF:

0.00

AC:

AN:

49722

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.69

CADD

Benign

4.7

(source)

DANN

Benign

0.83

PhyloP100

-3.3

Mutation Taster

=100/0

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000037

dbscSNV1_RF

Benign

0.0

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over