rs2236533

Variant names:

• chr10-44378768-G-A
• rs2236533
• NM_199168.4:c.180-45C>T

Variant summary

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

The NM_199168.4(CXCL12):​c.180-45C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.258 in 1,601,644 control chromosomes in the GnomAD database, including 57,009 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.22 (4658 hom., cov: 33)
  • Exomes 𝑓: 0.26 (52351 hom.)
• Consequence: CXCL12 NM_199168.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.667
• Publications: 9 publications found

Genes affected

CXCL12 (HGNC:10672): (C-X-C motif chemokine ligand 12) This antimicrobial gene encodes a stromal cell-derived alpha chemokine member of the intercrine family. The encoded protein functions as the ligand for the G-protein coupled receptor, chemokine (C-X-C motif) receptor 4, and plays a role in many diverse cellular functions, including embryogenesis, immune surveillance, inflammation response, tissue homeostasis, and tumor growth and metastasis. Mutations in this gene are associated with resistance to human immunodeficiency virus type 1 infections. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Sep 2014]

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 10-44378768-G-A is Benign according to our data. Variant chr10-44378768-G-A is described in ClinVar as Benign. ClinVar VariationId is 1246518.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.382 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CXCL12	NM_199168.4	c.180-45C>T		intron_variant	Intron 2 of 2	ENST00000343575.11	NP_954637.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CXCL12	ENST00000343575.11	c.180-45C>T		intron_variant	Intron 2 of 2	1	NM_199168.4	ENSP00000339913.6

Frequencies

GnomAD3 genomes AF: 0.224 AC: 34120 AN: 152070 Hom.: 4657 Cov.: 33

Gnomad AFR AF: 0.0852

Gnomad AMI AF: 0.284

Gnomad AMR AF: 0.390

Gnomad ASJ AF: 0.234

Gnomad EAS AF: 0.139

Gnomad SAS AF: 0.221

Gnomad FIN AF: 0.341

Gnomad MID AF: 0.191

Gnomad NFE AF: 0.259

Gnomad OTH AF: 0.252

GnomAD2 exomes AF: 0.277 AC: 69506 AN: 250952 AF XY: 0.271

Gnomad AFR exome AF: 0.0778

Gnomad AMR exome AF: 0.500

Gnomad ASJ exome AF: 0.234

Gnomad EAS exome AF: 0.133

Gnomad FIN exome AF: 0.335

Gnomad NFE exome AF: 0.267

Gnomad OTH exome AF: 0.259

GnomAD4 exome AF: 0.262 AC: 379416 AN: 1449456 Hom.: 52351 Cov.: 27 AF XY: 0.260 AC XY: 187669 AN XY: 721928

African (AFR) AF: 0.0748 AC: 2482 AN: 33176

American (AMR) AF: 0.479 AC: 21388 AN: 44690

Ashkenazi Jewish (ASJ) AF: 0.238 AC: 6196 AN: 26048

East Asian (EAS) AF: 0.139 AC: 5502 AN: 39608

South Asian (SAS) AF: 0.234 AC: 20089 AN: 86012

European-Finnish (FIN) AF: 0.326 AC: 17340 AN: 53238

Middle Eastern (MID) AF: 0.185 AC: 1063 AN: 5732

European-Non Finnish (NFE) AF: 0.264 AC: 290719 AN: 1100952

Other (OTH) AF: 0.244 AC: 14637 AN: 60000

GnomAD4 genome AF: 0.224 AC: 34124 AN: 152188 Hom.: 4658 Cov.: 33 AF XY: 0.231 AC XY: 17193 AN XY: 74402

African (AFR) AF: 0.0850 AC: 3533 AN: 41544

American (AMR) AF: 0.390 AC: 5960 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.234 AC: 813 AN: 3472

East Asian (EAS) AF: 0.138 AC: 715 AN: 5178

South Asian (SAS) AF: 0.220 AC: 1060 AN: 4820

European-Finnish (FIN) AF: 0.341 AC: 3606 AN: 10588

Middle Eastern (MID) AF: 0.199 AC: 58 AN: 292

European-Non Finnish (NFE) AF: 0.259 AC: 17593 AN: 67988

Other (OTH) AF: 0.250 AC: 527 AN: 2112

Alfa AF: 0.258 Hom.: 1821

Bravo AF: 0.225

Asia WGS AF: 0.177 AC: 614 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Nov 10, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	5.9
DANN	Benign	0.77
PhyloP100		0.67
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: rs2236533; hg19: chr10-44874216;