chr12-6800222-A-G

Variant names:

• chr12-6800222-A-G
• rs2365568
• NM_000616.5:c.49+35A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000616.5(CD4):​c.49+35A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.928 in 1,612,746 control chromosomes in the GnomAD database, including 695,900 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.94 (67476 hom., cov: 28)
  • Exomes 𝑓: 0.93 (628424 hom.)
• Consequence: CD4 NM_000616.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 1.42
• Publications: 10 publications found

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

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BP6: Variant 12-6800222-A-G is Benign according to our data. Variant chr12-6800222-A-G is described in ClinVar as Benign. ClinVar VariationId is 1192705.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.978 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000616.5. 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
	CD4	NM_000616.5	MANE Select	c.49+35A>G		intron	N/A	NP_000607.1	P01730
	CD4	NM_001382707.1		c.49+35A>G		intron	N/A	NP_001369636.1	P01730
	CD4	NM_001382714.1		c.49+35A>G		intron	N/A	NP_001369643.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CD4	ENST00000011653.9	TSL:1 MANE Select	c.49+35A>G		intron	N/A	ENSP00000011653.4	P01730
	CD4	ENST00000541982.5	TSL:1	c.49+35A>G		intron	N/A	ENSP00000445167.1	F5H480
	CD4	ENST00000538827.5	TSL:1	n.127+10560A>G		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.942 AC: 142895 AN: 151718 Hom.: 67426 Cov.: 28

Gnomad AFR AF: 0.986

Gnomad AMI AF: 0.948

Gnomad AMR AF: 0.857

Gnomad ASJ AF: 0.929

Gnomad EAS AF: 0.999

Gnomad SAS AF: 0.981

Gnomad FIN AF: 0.955

Gnomad MID AF: 0.962

Gnomad NFE AF: 0.926

Gnomad OTH AF: 0.944

GnomAD2 exomes AF: 0.920 AC: 231122 AN: 251308 AF XY: 0.928

Gnomad AFR exome AF: 0.986

Gnomad AMR exome AF: 0.743

Gnomad ASJ exome AF: 0.936

Gnomad EAS exome AF: 1.00

Gnomad FIN exome AF: 0.950

Gnomad NFE exome AF: 0.928

Gnomad OTH exome AF: 0.923

GnomAD4 exome AF: 0.927 AC: 1353678 AN: 1460910 Hom.: 628424 Cov.: 37 AF XY: 0.929 AC XY: 675070 AN XY: 726828

African (AFR) AF: 0.988 AC: 33079 AN: 33472

American (AMR) AF: 0.757 AC: 33826 AN: 44702

Ashkenazi Jewish (ASJ) AF: 0.933 AC: 24389 AN: 26132

East Asian (EAS) AF: 1.00 AC: 39684 AN: 39694

South Asian (SAS) AF: 0.976 AC: 84148 AN: 86238

European-Finnish (FIN) AF: 0.948 AC: 50613 AN: 53368

Middle Eastern (MID) AF: 0.960 AC: 5536 AN: 5766

European-Non Finnish (NFE) AF: 0.923 AC: 1026060 AN: 1111170

Other (OTH) AF: 0.933 AC: 56343 AN: 60368

GnomAD4 genome AF: 0.942 AC: 143003 AN: 151836 Hom.: 67476 Cov.: 28 AF XY: 0.943 AC XY: 69977 AN XY: 74186

African (AFR) AF: 0.986 AC: 40845 AN: 41442

American (AMR) AF: 0.856 AC: 13024 AN: 15214

Ashkenazi Jewish (ASJ) AF: 0.929 AC: 3219 AN: 3464

East Asian (EAS) AF: 0.999 AC: 5141 AN: 5144

South Asian (SAS) AF: 0.980 AC: 4714 AN: 4810

European-Finnish (FIN) AF: 0.955 AC: 10069 AN: 10548

Middle Eastern (MID) AF: 0.966 AC: 284 AN: 294

European-Non Finnish (NFE) AF: 0.926 AC: 62851 AN: 67902

Other (OTH) AF: 0.945 AC: 1993 AN: 2108

Alfa AF: 0.929 Hom.: 11425

Bravo AF: 0.933

Asia WGS AF: 0.988 AC: 3435 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Immunodeficiency 79 (1)
-	-	1	not provided (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	9.0
DANN	Benign	0.78
PhyloP100		1.4
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: rs2365568; hg19: chr12-6909388;