2-136114893-C-CTCAGACTCAGTGGAAACAGATGAATGTCCACCTCGCTTTCCTTTGGAGAGGATCTTGAGGCTGGACCCTCTGCTCACAGAGGTGAGTGCGTGCTGGGCAGAGGTTTTAAATTTGGCTCCAAGGAAAGCATAGAGGATGGGGT

Position:

• chr2-136114893-C-CTCAGACTCAGTGGAAACAGATGAATGTCCACCTCGCTTTCCTTTGGAGAGGATCTTGAGGCTGGACCCTCTGCTCACAGAGGTGAGTGCGTGCTGGGCAGAGGTTTTAAATTTGGCTCCAAGGAAAGCATAGAGGATGGGGT

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PVS1_Moderate PM2 PP5_Moderate

The NM_003467.3(CXCR4):​c.893_1034dupACCCCATCCTCTATGCTTTCCTTGGAGCCAAATTTAAAACCTCTGCCCAGCACGCACTCACCTCTGTGAGCAGAGGGTCCAGCCTCAAGATCCTCTCCAAAGGAAAGCGAGGTGGACATTCATCTGTTTCCACTGAGTCTGA​(p.Ser346fs) variant causes a frameshift, stop gained change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: CXCR4 NM_003467.3 frameshift, stop_gained
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 7.67

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.0236 CDS is truncated, and there are 0 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 2-136114893-C-CTCAGACTCAGTGGAAACAGATGAATGTCCACCTCGCTTTCCTTTGGAGAGGATCTTGAGGCTGGACCCTCTGCTCACAGAGGTGAGTGCGTGCTGGGCAGAGGTTTTAAATTTGGCTCCAAGGAAAGCATAGAGGATGGGGT is Pathogenic according to our data. Variant chr2-136114893-C-CTCAGACTCAGTGGAAACAGATGAATGTCCACCTCGCTTTCCTTTGGAGAGGATCTTGAGGCTGGACCCTCTGCTCACAGAGGTGAGTGCGTGCTGGGCAGAGGTTTTAAATTTGGCTCCAAGGAAAGCATAGAGGATGGGGT is described in ClinVar as [Pathogenic]. Clinvar id is 1513755.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CXCR4	NM_003467.3	c.893_1034dupACCCCATCCTCTATGCTTTCCTTGGAGCCAAATTTAAAACCTCTGCCCAGCACGCACTCACCTCTGTGAGCAGAGGGTCCAGCCTCAAGATCCTCTCCAAAGGAAAGCGAGGTGGACATTCATCTGTTTCCACTGAGTCTGA	p.Ser346fs	frameshift_variant, stop_gained	2/2	ENST00000241393.4	NP_003458.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CXCR4	ENST00000241393.4	c.893_1034dupACCCCATCCTCTATGCTTTCCTTGGAGCCAAATTTAAAACCTCTGCCCAGCACGCACTCACCTCTGTGAGCAGAGGGTCCAGCCTCAAGATCCTCTCCAAAGGAAAGCGAGGTGGACATTCATCTGTTTCCACTGAGTCTGA	p.Ser346fs	frameshift_variant, stop_gained	2/2	1	NM_003467.3	ENSP00000241393.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Warts, hypogammaglobulinemia, infections, and myelokathexis Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Aug 30, 2022

For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. Experimental studies have shown that this frameshift affects CXCR4 function (external communication). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. ClinVar contains an entry for this variant (Variation ID: 1513755). This frameshift has been observed in individual(s) with clinical features consistent with WHIM syndrome (Invitae). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change results in a frameshift in the CXCR4 gene (p.Ser346Profs*12). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 7 amino acid(s) of the CXCR4 protein and extend the protein by 4 additional amino acid residues. -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr2-136872463;