Genetic Variant CD4:p.Gly236Gly (chr12-6816156-C-T) – ACMG Classification: Benign (-11 pts)

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 0P and 11B. BP4_StrongBP6_ModerateBP7BS2

The NM_000616.5(CD4):c.708C>T(p.Gly236Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000312 in 1,614,172 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.00097 ( 1 hom., cov: 32)

Exomes 𝑓: 0.00024 ( 3 hom. )

Consequence

CD4
NM_000616.5 synonymous

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: -1.42

Publications

3 publications found

Variant links:

Genes affected

CD4 (HGNC:1678): (CD4 molecule) This gene encodes the CD4 membrane glycoprotein of T lymphocytes. The CD4 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 II MHC molecules. The CD4 antigen is also a primary receptor for entry of the human immunodeficiency virus through interactions with the HIV Env gp120 subunit. This gene is expressed not only in T lymphocytes, but also in B cells, macrophages, granulocytes, as well as in various regions of the brain. The protein functions to initiate or augment the early phase of T-cell activation, and may function as an important mediator of indirect neuronal damage in infectious and immune-mediated diseases of the central nervous system. Multiple alternatively spliced transcript variants encoding different isoforms have been identified in this gene. [provided by RefSeq, May 2020]

CD4 Gene-Disease associations (from GenCC):

immunodeficiency 79
Inheritance: AR, Unknown Classification: MODERATE, LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)

CD4 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -11 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.53).

BP6

Variant 12-6816156-C-T is Benign according to our data. Variant chr12-6816156-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 2642636.Status of the report is criteria_provided_single_submitter, 1 stars.

BP7

Synonymous conserved (PhyloP=-1.42 with no splicing effect.

BS2

High Homozygotes in GnomAdExome4 at 3 AR,Unknown gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CD4	NM_000616.5 link	c.708C>T	p.Gly236Gly	synonymous_variant	Exon 6 of 10	ENST00000011653.9	NP_000607.1	P01730B4DT49A0A4Y5UGE4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CD4	ENST00000011653.9 link	c.708C>T	p.Gly236Gly	synonymous_variant	Exon 6 of 10	1	NM_000616.5	ENSP00000011653.4		P01730

Frequencies

GnomAD3 genomes

AF:

0.000986

AC:

150

AN:

152172

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00304

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000720

Gnomad ASJ

AF:

0.000576

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000147

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000306

AC:

AN:

251458

AF XY:

0.000221

show subpopulations

Gnomad AFR exome

AF:

0.00203

Gnomad AMR exome

AF:

0.000318

Gnomad ASJ exome

AF:

0.000695

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000132

Gnomad OTH exome

AF:

0.000815

GnomAD4 exome

AF:

0.000244

AC:

357

AN:

1461882

Hom.:

Cov.:

AF XY:

0.000252

AC XY:

183

AN XY:

727246

show subpopulations

African (AFR)

AF:

0.00427

AC:

143

AN:

33478

American (AMR)

AF:

0.000291

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.000497

AC:

AN:

26134

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.000185

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.0000187

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.00381

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0000881

AC:

AN:

1112004

Other (OTH)

AF:

0.000844

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.484

Heterozygous variant carriers

103

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000965

AC:

147

AN:

152290

Hom.:

Cov.:

AF XY:

0.000967

AC XY:

AN XY:

74464

show subpopulations

African (AFR)

AF:

0.00296

AC:

123

AN:

41546

American (AMR)

AF:

0.000719

AC:

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.000576

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5196

South Asian (SAS)

AF:

0.000207

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10616

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000147

AC:

AN:

68016

Other (OTH)

AF:

0.00

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000432

Hom.:

Bravo

AF:

0.000873

Asia WGS

AF:

0.000866

AC:

AN:

3478

EpiCase

AF:

0.0000545

EpiControl

AF:

0.000178

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Benign:1

Feb 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

CD4: BP4, BP7 -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.53

CADD

Benign

4.0

(source)

DANN

Benign

0.54

PhyloP100

-1.4

Mutation Taster

=100/0

polymorphism

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over