rs2471859

Variant names:

• chr2-136116434-A-G
• rs2471859
• NM_003467.3:c.16-522T>C

Variant summary

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

The NM_003467.3(CXCR4):​c.16-522T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.302 in 151,910 control chromosomes in the GnomAD database, including 8,723 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency: Genomes: 𝑓 0.30 (8723 hom., cov: 31)
• Consequence: CXCR4 NM_003467.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.570
• Publications: 5 publications found

Genes affected

CXCR4 (HGNC:2561): (C-X-C motif chemokine receptor 4) This gene encodes a CXC chemokine receptor specific for stromal cell-derived factor-1. The protein has 7 transmembrane regions and is located on the cell surface. It acts with the CD4 protein to support HIV entry into cells and is also highly expressed in breast cancer cells. Mutations in this gene have been associated with WHIM (warts, hypogammaglobulinemia, infections, and myelokathexis) syndrome. Alternate transcriptional splice variants, encoding different isoforms, have been characterized. [provided by RefSeq, Jul 2008]

CXCR4 Gene-Disease associations (from GenCC):

• WHIM syndrome

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• WHIM syndrome 1

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
• WHIM syndrome

  Inheritance: AD Classification: MODERATE, SUPPORTIVE Submitted by: Orphanet, Ambry Genetics

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 2-136116434-A-G is Benign according to our data. Variant chr2-136116434-A-G is described in ClinVar as Benign. ClinVar VariationId is 1279307.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.52 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003467.3. 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
	CXCR4	NM_003467.3	MANE Select	c.16-522T>C		intron	N/A	NP_003458.1	P61073-1
	CXCR4	NM_001348056.2		c.228+42T>C		intron	N/A	NP_001334985.1	A0A0U3GXA9
	CXCR4	NM_001348059.2		c.114+156T>C		intron	N/A	NP_001334988.1	A0A0U3FJG0

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CXCR4	ENST00000241393.4	TSL:1 MANE Select	c.16-522T>C		intron	N/A	ENSP00000241393.3	P61073-1
	CXCR4	ENST00000466288.1	TSL:1	c.-30-522T>C		intron	N/A	ENSP00000512430.1	A0A8Q3WLL1
	CXCR4	ENST00000696136.1		c.3+42T>C		intron	N/A	ENSP00000512428.1	A0A8Q3WL10

Frequencies

GnomAD3 genomes AF: 0.302 AC: 45872 AN: 151794 Hom.: 8701 Cov.: 31

Gnomad AFR AF: 0.526

Gnomad AMI AF: 0.310

Gnomad AMR AF: 0.287

Gnomad ASJ AF: 0.151

Gnomad EAS AF: 0.0377

Gnomad SAS AF: 0.268

Gnomad FIN AF: 0.127

Gnomad MID AF: 0.123

Gnomad NFE AF: 0.229

Gnomad OTH AF: 0.268

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.302 AC: 45952 AN: 151910 Hom.: 8723 Cov.: 31 AF XY: 0.295 AC XY: 21911 AN XY: 74254

African (AFR) AF: 0.526 AC: 21759 AN: 41370

American (AMR) AF: 0.286 AC: 4369 AN: 15256

Ashkenazi Jewish (ASJ) AF: 0.151 AC: 522 AN: 3466

East Asian (EAS) AF: 0.0378 AC: 195 AN: 5162

South Asian (SAS) AF: 0.269 AC: 1295 AN: 4812

European-Finnish (FIN) AF: 0.127 AC: 1342 AN: 10562

Middle Eastern (MID) AF: 0.133 AC: 39 AN: 294

European-Non Finnish (NFE) AF: 0.229 AC: 15589 AN: 67968

Other (OTH) AF: 0.265 AC: 560 AN: 2110

Alfa AF: 0.265 Hom.: 1014

Bravo AF: 0.323

Asia WGS AF: 0.172 AC: 598 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	4.8
DANN	Benign	0.44
PhyloP100		-0.57
PromoterAI		-0.0098	Neutral
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs2471859; hg19: chr2-136874004;