3-46408806-A-G

Position:

• chr3-46408806-A-G

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_003965.5(CCRL2):​c.727A>G​(p.Ile243Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0893 in 1,614,098 control chromosomes in the GnomAD database, including 7,853 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.068 (526 hom., cov: 33)
  • Exomes 𝑓: 0.092 (7327 hom.)
• Consequence: CCRL2 NM_003965.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.00400

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 Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0012773871).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.186 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CCRL2	NM_003965.5	c.727A>G	p.Ile243Val	missense_variant	2/2	ENST00000399036.4	NP_003956.2
CCRL2	NM_001130910.2	c.763A>G	p.Ile255Val	missense_variant	2/2		NP_001124382.1
CCRL2	XM_011534208.2	c.727A>G	p.Ile243Val	missense_variant	3/3		XP_011532510.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CCRL2	ENST00000399036.4	c.727A>G	p.Ile243Val	missense_variant	2/2	1	NM_003965.5	ENSP00000381994	P2
CCRL2	ENST00000357392.4	c.763A>G	p.Ile255Val	missense_variant	2/2	1		ENSP00000349967	A2
CCRL2	ENST00000400880.3	c.727A>G	p.Ile243Val	missense_variant	2/2	1		ENSP00000383677	P2
CCRL2	ENST00000400882.2	c.727A>G	p.Ile243Val	missense_variant	1/1			ENSP00000383678	P2

Frequencies

GnomAD3 genomes AF: 0.0679 AC: 10327 AN: 152142 Hom.: 526 Cov.: 33

Gnomad AFR AF: 0.0153

Gnomad AMI AF: 0.128

Gnomad AMR AF: 0.0371

Gnomad ASJ AF: 0.0608

Gnomad EAS AF: 0.0383

Gnomad SAS AF: 0.195

Gnomad FIN AF: 0.154

Gnomad MID AF: 0.111

Gnomad NFE AF: 0.0862

Gnomad OTH AF: 0.0598

GnomAD3 exomes AF: 0.0926 AC: 23105 AN: 249538 Hom.: 1529 AF XY: 0.101 AC XY: 13703 AN XY: 135378

Gnomad AFR exome AF: 0.0126

Gnomad AMR exome AF: 0.0403

Gnomad ASJ exome AF: 0.0608

Gnomad EAS exome AF: 0.0482

Gnomad SAS exome AF: 0.209

Gnomad FIN exome AF: 0.154

Gnomad NFE exome AF: 0.0867

Gnomad OTH exome AF: 0.0824

GnomAD4 exome AF: 0.0915 AC: 133802 AN: 1461838 Hom.: 7327 Cov.: 35 AF XY: 0.0960 AC XY: 69823 AN XY: 727230

Gnomad4 AFR exome AF: 0.0124

Gnomad4 AMR exome AF: 0.0403

Gnomad4 ASJ exome AF: 0.0625

Gnomad4 EAS exome AF: 0.0382

Gnomad4 SAS exome AF: 0.209

Gnomad4 FIN exome AF: 0.151

Gnomad4 NFE exome AF: 0.0870

Gnomad4 OTH exome AF: 0.0819

GnomAD4 genome AF: 0.0678 AC: 10320 AN: 152260 Hom.: 526 Cov.: 33 AF XY: 0.0730 AC XY: 5432 AN XY: 74420

Gnomad4 AFR AF: 0.0152

Gnomad4 AMR AF: 0.0369

Gnomad4 ASJ AF: 0.0608

Gnomad4 EAS AF: 0.0384

Gnomad4 SAS AF: 0.196

Gnomad4 FIN AF: 0.154

Gnomad4 NFE AF: 0.0862

Gnomad4 OTH AF: 0.0587

Alfa AF: 0.0790 Hom.: 833

Bravo AF: 0.0534

TwinsUK AF: 0.0836 AC: 310

ALSPAC AF: 0.0861 AC: 332

ESP6500AA AF: 0.0170 AC: 66

ESP6500EA AF: 0.0836 AC: 690

ExAC AF: 0.0942 AC: 11391

Asia WGS AF: 0.0930 AC: 323 AN: 3478

EpiCase AF: 0.0818

EpiControl AF: 0.0816

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.74	T
BayesDel_noAF	Benign	-0.69
CADD	Benign	0.62
DANN	Benign	0.89
DEOGEN2	Benign	0.034	T;.;T;T
Eigen	Benign	-0.81
Eigen_PC	Benign	-0.82
FATHMM_MKL	Benign	0.062	N
LIST_S2	Benign	0.57	.;T;.;T
MetaRNN	Benign	0.0013	T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.2	L;.;L;L
MutationTaster	Benign	1.0	P;P;P;P
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-0.72	N;N;N;N
REVEL	Benign	0.016
Sift	Benign	0.32	T;T;T;T
Sift4G	Benign	0.33	T;T;T;T
Polyphen		0.046	B;B;B;B
Vest4		0.073
MPC		0.033
ClinPred		0.0023	T
GERP RS		0.16
Varity_R		0.065
gMVP		0.26

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: rs3204850; hg19: chr3-46450297; COSMIC: COSV62193319; COSMIC: COSV62193319;