rs4796195

Positions:

• chr17-36212480-G-A

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 4P and 8B. PVS1_Strong BA1

The ENST00000620250.1(CCL4L2):​c.192-2G>A variant causes a splice acceptor, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.766 in 1,578,468 control chromosomes in the GnomAD database, including 458,970 homozygotes. In-silico tool predicts a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.71 (33451 hom., cov: 37)
  • Exomes 𝑓: 0.77 (425519 hom.)
• Consequence: CCL4L2 ENST00000620250.1 splice_acceptor, intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.43

Genes affected

CCL4L2 (HGNC:24066): (C-C motif chemokine ligand 4 like 2) This gene is one of several cytokine genes that are clustered on the q-arm of chromosome 17. Cytokines are a family of secreted proteins that function in inflammatory and immunoregulatory processes. The protein encoded by this family member is similar to the chemokine (C-C motif) ligand 4 product, which inhibits HIV entry by binding to the cellular receptor CCR5. The copy number of this gene varies among individuals, where most individuals have one to five copies. This gene copy contains a non-consensus splice acceptor site at the 3' terminal exon found in other highly similar gene copies, and it thus uses other alternative splice sites for the 3' terminal exon, resulting in multiple transcript variants. [provided by RefSeq, Apr 2014]

CCL4L2 (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -4 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 1.4193548 fraction of the gene. Cryptic splice site detected, with MaxEntScore 9.6, offset of 0 (no position change), new splice context is: gtctgctccttgttctacAGatt. Cryptic site results in inframe change. If cryptic site found is not functional and variant results in exon loss, it results in frameshift change.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.79 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CCL4L2	NM_001291475.2	c.*57G>A		3_prime_UTR_variant	3/3	ENST00000617405.5	NP_001278404.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CCL4L2	ENST00000617405.5	c.*57G>A		3_prime_UTR_variant	3/3	1	NM_001291475.2	ENSP00000483330.1
CCL4L2	ENST00000620250.1	c.192-2G>A		splice_acceptor_variant, intron_variant		1		ENSP00000483609.1
CCL4L2	ENST00000620576.4	c.192-17G>A		intron_variant		1		ENSP00000479354.1

Frequencies

GnomAD3 genomes AF: 0.706 AC: 103414 AN: 146516 Hom.: 33445 Cov.: 37

Gnomad AFR AF: 0.572

Gnomad AMI AF: 0.820

Gnomad AMR AF: 0.643

Gnomad ASJ AF: 0.777

Gnomad EAS AF: 0.616

Gnomad SAS AF: 0.674

Gnomad FIN AF: 0.766

Gnomad MID AF: 0.791

Gnomad NFE AF: 0.796

Gnomad OTH AF: 0.720

GnomAD3 exomes AF: 0.00505 AC: 633 AN: 125266 Hom.: 234 AF XY: 0.00456 AC XY: 299 AN XY: 65588

Gnomad AFR exome AF: 0.0237

Gnomad AMR exome AF: 0.00278

Gnomad ASJ exome AF: 0.000571

Gnomad EAS exome AF: 0.00243

Gnomad SAS exome AF: 0.00598

Gnomad FIN exome AF: 0.00633

Gnomad NFE exome AF: 0.00109

Gnomad OTH exome AF: 0.00545

GnomAD4 exome AF: 0.773 AC: 1106125 AN: 1431838 Hom.: 425519 Cov.: 90 AF XY: 0.771 AC XY: 549227 AN XY: 712058

Gnomad4 AFR exome AF: 0.569

Gnomad4 AMR exome AF: 0.604

Gnomad4 ASJ exome AF: 0.790

Gnomad4 EAS exome AF: 0.605

Gnomad4 SAS exome AF: 0.682

Gnomad4 FIN exome AF: 0.774

Gnomad4 NFE exome AF: 0.799

Gnomad4 OTH exome AF: 0.754

GnomAD4 genome AF: 0.706 AC: 103476 AN: 146630 Hom.: 33451 Cov.: 37 AF XY: 0.703 AC XY: 50201 AN XY: 71460

Gnomad4 AFR AF: 0.572

Gnomad4 AMR AF: 0.643

Gnomad4 ASJ AF: 0.777

Gnomad4 EAS AF: 0.615

Gnomad4 SAS AF: 0.675

Gnomad4 FIN AF: 0.766

Gnomad4 NFE AF: 0.796

Gnomad4 OTH AF: 0.721

Alfa AF: 0.727 Hom.: 2996

ExAC AF: 0.00479 AC: 317

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.41
CADD	Benign	14
DANN	Benign	0.85
Eigen	Benign	0.11
Eigen_PC	Benign	-0.14
FATHMM_MKL	Benign	0.0055	N
GERP RS		2.9

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

Publications

LitVar

Other links and lift over

dbSNP: rs4796195; hg19: chr17-34539882;