3-46408815-G-A

Position:

• chr3-46408815-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_003965.5(CCRL2):​c.736G>A​(p.Val246Ile) 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. 15/21 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: 1.43

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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.2981261).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CCRL2	NM_003965.5	c.736G>A	p.Val246Ile	missense_variant	2/2	ENST00000399036.4
CCRL2	NM_001130910.2	c.772G>A	p.Val258Ile	missense_variant	2/2
CCRL2	XM_011534208.2	c.736G>A	p.Val246Ile	missense_variant	3/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CCRL2	ENST00000399036.4	c.736G>A	p.Val246Ile	missense_variant	2/2	1	NM_003965.5	P2
CCRL2	ENST00000357392.4	c.772G>A	p.Val258Ile	missense_variant	2/2	1		A2
CCRL2	ENST00000400880.3	c.736G>A	p.Val246Ile	missense_variant	2/2	1		P2
CCRL2	ENST00000400882.2	c.736G>A	p.Val246Ile	missense_variant	1/1			P2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 33

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

Jun 29, 2023

The c.772G>A (p.V258I) alteration is located in exon 2 (coding exon 2) of the CCRL2 gene. This alteration results from a G to A substitution at nucleotide position 772, causing the valine (V) at amino acid position 258 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	0.11
BayesDel_addAF	Benign	-0.053	T
BayesDel_noAF	Benign	-0.31
CADD	Benign	17
DANN	Uncertain	1.0
DEOGEN2	Benign	0.026	T;.;T;T
Eigen	Benign	-0.043
Eigen_PC	Benign	-0.12
FATHMM_MKL	Benign	0.60	D
LIST_S2	Benign	0.64	.;T;.;T
M_CAP	Benign	0.034	D
MetaRNN	Benign	0.30	T;T;T;T
MetaSVM	Benign	-0.65	T
MutationAssessor	Benign	1.9	L;.;L;L
MutationTaster	Benign	1.0	N;N;N;N
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-0.70	N;N;N;N
REVEL	Benign	0.28
Sift	Uncertain	0.010	D;T;D;D
Sift4G	Benign	0.15	T;T;T;T
Polyphen		0.79	P;P;P;P
Vest4		0.13
MutPred		0.55		Loss of catalytic residue at V246 (P = 0.0093);.;Loss of catalytic residue at V246 (P = 0.0093);Loss of catalytic residue at V246 (P = 0.0093);
MVP		0.58
MPC		0.053
ClinPred		0.63	D
GERP RS		2.4
Varity_R		0.11
gMVP		0.25

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr3-46450306;