2-136114915-G-C

Variant names:

• chr2-136114915-G-C
• rs104893626
• NM_003467.3:c.1013C>G

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1_Strong PS3 PM2 PP5_Very_Strong

The NM_003467.3(CXCR4):​c.1013C>G​(p.Ser338*) variant causes a stop gained change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV000898643: Additional functional studies have shown a deleterious effect of this variant (Balabanian 2005 PMID:15536153, Lagane 2008 PMID:18436740).; SCV001472850: "Indeed, functional characterization of patient cells or cultured cells expressing the p.Ser338Ter variant suggests the variant protein exhibits defective internalization, aberrant interactions with binding partners, and increased signaling activity (Balabanian 2005, Lagane 2008, Tassone 2009)."; SCV001792959: Published functional studies demonstrate a damaging effect with delayed or failed receptor internalization (Balabanian et al., 2005); PMID:19321197, 15536153, 23009153, 19878273, 25819228, 25371371, 18436740, 26997321, 17087743; SCV003919869: Additional functional studies have shown a deleterious effect of this variant (Balabanian 2005 PMID:15536153, Lagane 2008 PMID:18436740).".

• Frequency: Genomes: not found (cov: 32)
• Consequence: CXCR4 NM_003467.3 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:6
• Conservation: PhyloP100: 9.60
• Publications: 98 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: Pathogenic. The variant received 18 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. There are 16 pathogenic variants in the truncated region.
• PS3: PS3 evidence extracted from ClinVar submissions: SCV000898643: Additional functional studies have shown a deleterious effect of this variant (Balabanian 2005 PMID:15536153, Lagane 2008 PMID:18436740).; SCV001472850: "Indeed, functional characterization of patient cells or cultured cells expressing the p.Ser338Ter variant suggests the variant protein exhibits defective internalization, aberrant interactions with binding partners, and increased signaling activity (Balabanian 2005, Lagane 2008, Tassone 2009)."; SCV001792959: Published functional studies demonstrate a damaging effect with delayed or failed receptor internalization (Balabanian et al., 2005); PMID: 19321197, 15536153, 23009153, 19878273, 25819228, 25371371, 18436740, 26997321, 17087743; SCV003919869: Additional functional studies have shown a deleterious effect of this variant (Balabanian 2005 PMID:15536153, Lagane 2008 PMID:18436740).
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 2-136114915-G-C is Pathogenic according to our data. Variant chr2-136114915-G-C is described in ClinVar as Pathogenic. ClinVar VariationId is 14023.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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.1013C>G	p.Ser338*	stop_gained	Exon 2 of 2	NP_003458.1	P61073-1
	CXCR4	NM_001348056.2		c.1226C>G	p.Ser409*	stop_gained	Exon 3 of 3	NP_001334985.1	A0A0U3GXA9
	CXCR4	NM_001348059.2		c.1112C>G	p.Ser371*	stop_gained	Exon 3 of 3	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.1013C>G	p.Ser338*	stop_gained	Exon 2 of 2	ENSP00000241393.3	P61073-1
	CXCR4	ENST00000466288.1	TSL:1	c.968C>G	p.Ser323*	stop_gained	Exon 2 of 2	ENSP00000512430.1	A0A8Q3WLL1
	CXCR4	ENST00000409817.1	TSL:6	c.1025C>G	p.Ser342*	stop_gained	Exon 1 of 1	ENSP00000386884.1	P61073-2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
3	-	-	WHIM syndrome 1 (3)
2	-	-	not provided (2)
1	-	-	Warts, hypogammaglobulinemia, infections, and myelokathexis (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.58	D
BayesDel_noAF	Pathogenic	0.60
CADD	Pathogenic	37
DANN	Uncertain	0.99
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.90
FATHMM_MKL	Pathogenic	0.98	D
PhyloP100		9.6
Vest4		0.81
GERP RS		6.0
Mutation Taster		=0/200	disease causing (ClinVar)

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: rs104893626; hg19: chr2-136872485; COSMIC: COSV54009912;