12-6814120-C-G

Variant names:

• chr12-6814120-C-G
• rs10849523
• NM_000616.5:c.215-22C>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000616.5(CD4):​c.215-22C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0555 in 1,610,394 control chromosomes in the GnomAD database, including 5,143 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.10 (1504 hom., cov: 31)
  • Exomes 𝑓: 0.050 (3639 hom.)
• Consequence: CD4 NM_000616.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.10
• Publications: 6 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: AR, Unknown Classification: MODERATE, LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.241 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CD4	NM_000616.5	MANE Select	c.215-22C>G		intron	N/A	NP_000607.1
	CD4	NM_001382707.1		c.215-22C>G		intron	N/A	NP_001369636.1
	CD4	NM_001382714.1		c.50-22C>G		intron	N/A	NP_001369643.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CD4	ENST00000011653.9	TSL:1 MANE Select	c.215-22C>G		intron	N/A	ENSP00000011653.4
	CD4	ENST00000541982.5	TSL:1	c.50-22C>G		intron	N/A	ENSP00000445167.1
	CD4	ENST00000538827.5	TSL:1	n.128-22C>G		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.105 AC: 15913 AN: 151946 Hom.: 1500 Cov.: 31

Gnomad AFR AF: 0.245

Gnomad AMI AF: 0.0921

Gnomad AMR AF: 0.0596

Gnomad ASJ AF: 0.0455

Gnomad EAS AF: 0.166

Gnomad SAS AF: 0.168

Gnomad FIN AF: 0.0471

Gnomad MID AF: 0.0506

Gnomad NFE AF: 0.0335

Gnomad OTH AF: 0.0921

GnomAD2 exomes AF: 0.0746 AC: 18600 AN: 249284 AF XY: 0.0752

Gnomad AFR exome AF: 0.251

Gnomad AMR exome AF: 0.0327

Gnomad ASJ exome AF: 0.0480

Gnomad EAS exome AF: 0.162

Gnomad FIN exome AF: 0.0411

Gnomad NFE exome AF: 0.0372

Gnomad OTH exome AF: 0.0593

GnomAD4 exome AF: 0.0503 AC: 73374 AN: 1458330 Hom.: 3639 Cov.: 31 AF XY: 0.0526 AC XY: 38137 AN XY: 725428

African (AFR) AF: 0.248 AC: 8267 AN: 33318

American (AMR) AF: 0.0351 AC: 1557 AN: 44422

Ashkenazi Jewish (ASJ) AF: 0.0485 AC: 1257 AN: 25894

East Asian (EAS) AF: 0.176 AC: 6970 AN: 39650

South Asian (SAS) AF: 0.146 AC: 12576 AN: 85958

European-Finnish (FIN) AF: 0.0410 AC: 2185 AN: 53232

Middle Eastern (MID) AF: 0.0703 AC: 404 AN: 5750

European-Non Finnish (NFE) AF: 0.0327 AC: 36261 AN: 1109896

Other (OTH) AF: 0.0647 AC: 3897 AN: 60210

GnomAD4 genome AF: 0.105 AC: 15950 AN: 152064 Hom.: 1504 Cov.: 31 AF XY: 0.107 AC XY: 7960 AN XY: 74340

African (AFR) AF: 0.245 AC: 10143 AN: 41416

American (AMR) AF: 0.0595 AC: 909 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.0455 AC: 158 AN: 3472

East Asian (EAS) AF: 0.167 AC: 864 AN: 5166

South Asian (SAS) AF: 0.167 AC: 805 AN: 4816

European-Finnish (FIN) AF: 0.0471 AC: 499 AN: 10600

Middle Eastern (MID) AF: 0.0510 AC: 15 AN: 294

European-Non Finnish (NFE) AF: 0.0335 AC: 2275 AN: 68002

Other (OTH) AF: 0.0940 AC: 198 AN: 2106

Alfa AF: 0.0233 Hom.: 21

Bravo AF: 0.109

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	3.3
DANN	Benign	0.36
PhyloP100		1.1
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: rs10849523; hg19: chr12-6923286; COSMIC: COSV50592040;