3-46408395-C-A

Position:

• chr3-46408395-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_003965.5(CCRL2):​c.316C>A​(p.Leu106Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: CCRL2 NM_003965.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -1.26

Genes affected

CCRL2 (HGNC:1612): (C-C motif chemokine receptor like 2) This gene encodes a chemokine receptor like protein, which is predicted to be a seven transmembrane protein and most closely related to CCR1. Chemokines and their receptors mediated signal transduction are critical for the recruitment of effector immune cells to the site of inflammation. This gene is expressed at high levels in primary neutrophils and primary monocytes, and is further upregulated on neutrophil activation and during monocyte to macrophage differentiation. The function of this gene is unknown. This gene is mapped to the region where the chemokine receptor gene cluster is located. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.09730196).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CCRL2	NM_003965.5	c.316C>A	p.Leu106Ile	missense_variant	2/2	ENST00000399036.4
CCRL2	NM_001130910.2	c.352C>A	p.Leu118Ile	missense_variant	2/2
CCRL2	XM_011534208.2	c.316C>A	p.Leu106Ile	missense_variant	3/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CCRL2	ENST00000399036.4	c.316C>A	p.Leu106Ile	missense_variant	2/2	1	NM_003965.5	P2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 20, 2021

The c.352C>A (p.L118I) alteration is located in exon 2 (coding exon 2) of the CCRL2 gene. This alteration results from a C to A substitution at nucleotide position 352, causing the leucine (L) at amino acid position 118 to be replaced by an isoleucine (I). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.60
CADD	Benign	6.0
DANN	Uncertain	0.98
DEOGEN2	Benign	0.031	T;.;T;T;T
Eigen	Benign	-0.95
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.11	N
LIST_S2	Benign	0.52	.;T;.;T;T
M_CAP	Benign	0.010	T
MetaRNN	Benign	0.097	T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.4	L;.;L;.;L
MutationTaster	Benign	1.0	N;N;N;N
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-0.99	N;N;N;N;N
REVEL	Benign	0.024
Sift	Benign	0.23	T;T;T;T;T
Sift4G	Benign	0.38	T;T;T;T;T
Polyphen		0.49	P;B;P;.;P
Vest4		0.060
MutPred		0.38		Loss of glycosylation at K104 (P = 0.1129);.;Loss of glycosylation at K104 (P = 0.1129);Loss of glycosylation at K104 (P = 0.1129);Loss of glycosylation at K104 (P = 0.1129);
MVP		0.17
MPC		0.10
ClinPred		0.25	T
GERP RS		-3.6
Varity_R		0.10
gMVP		0.085

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: rs754286699; hg19: chr3-46449886;