2-136115979-A-G

Variant names:

• chr2-136115979-A-G
• rs2680880
• NM_003467.3:c.16-67T>C

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001008540.2(CXCR4):​c.-40T>C variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,459,854 control chromosomes in the GnomAD database, with no homozygous occurrence. 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: not found (cov: 31)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: CXCR4 NM_001008540.2 5_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.403
• Publications: 0 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001008540.2. 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.16-67T>C		intron	N/A	NP_003458.1	P61073-1
	CXCR4	NM_001008540.2		c.-40T>C		5_prime_UTR	Exon 1 of 1	NP_001008540.1	P61073-2
	CXCR4	NM_001348056.2		c.229-67T>C		intron	N/A	NP_001334985.1	A0A0U3GXA9

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CXCR4	ENST00000241393.4	TSL:1 MANE Select	c.16-67T>C		intron	N/A	ENSP00000241393.3	P61073-1
	CXCR4	ENST00000466288.1	TSL:1	c.-30-67T>C		intron	N/A	ENSP00000512430.1	A0A8Q3WLL1
	CXCR4	ENST00000409817.1	TSL:6	c.-40T>C		5_prime_UTR	Exon 1 of 1	ENSP00000386884.1	P61073-2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1459854 Hom.: 0 Cov.: 41 AF XY: 0.00000138 AC XY: 1 AN XY: 726124

African (AFR) AF: 0.0000299 AC: 1 AN: 33458

American (AMR) AF: 0.00 AC: 0 AN: 44570

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26122

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.00 AC: 0 AN: 85980

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52606

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000270 AC: 3 AN: 1111298

Other (OTH) AF: 0.00 AC: 0 AN: 60356

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.23
DANN	Benign	0.34
PhyloP100		-0.40
PromoterAI		-0.0022	Neutral

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: rs2680880; hg19: chr2-136873549;