dbSNP rs56127823: CCRL2:p.Tyr220Ser (chr3-46408738-A-C) – ACMG Classification: Uncertain_significance (4 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_003965.5(CCRL2):c.659A>C(p.Tyr220Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,780 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 13/21 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 variant affecting the same amino acid position, but resulting in a different missense (i.e. Y220C) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

CCRL2
NM_003965.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.987

Variant links:

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]

CCRL2 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.848

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CCRL2	NM_003965.5 link	c.659A>C	p.Tyr220Ser	missense_variant	Exon 2 of 2	ENST00000399036.4	NP_003956.2	O00421-1B2R8C0
CCRL2	NM_001130910.2 link	c.695A>C	p.Tyr232Ser	missense_variant	Exon 2 of 2		NP_001124382.1	O00421-2
CCRL2	XM_011534208.2 link	c.659A>C	p.Tyr220Ser	missense_variant	Exon 3 of 3		XP_011532510.1	O00421-1B2R8C0

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CCRL2	ENST00000399036.4 link	c.659A>C	p.Tyr220Ser	missense_variant	Exon 2 of 2	1	NM_003965.5	ENSP00000381994.3		O00421-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461780

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727212

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

8.99e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.16

BayesDel_addAF

Benign

-0.058

BayesDel_noAF

Benign

-0.32

CADD

Benign

5.8

DANN

Benign

0.76

DEOGEN2

Benign

0.32

T;.;T;T

Eigen

Benign

-0.62

Eigen_PC

Benign

-0.85

FATHMM_MKL

Benign

0.38

LIST_S2

Benign

0.65

.;T;.;T

M_CAP

Benign

0.022

MetaRNN

Pathogenic

0.85

D;D;D;D

MetaSVM

Benign

-0.97

MutationAssessor

Pathogenic

3.3

M;.;M;M

PrimateAI

Benign

0.24

PROVEAN

Pathogenic

-6.8

D;D;D;D

REVEL

Benign

0.22

Sift

Benign

0.060

T;T;T;T

Sift4G

Uncertain

0.034

D;D;D;D

Polyphen

0.69

P;P;P;P

Vest4

0.24

MutPred

0.83

Loss of ubiquitination at K225 (P = 0.0839);.;Loss of ubiquitination at K225 (P = 0.0839);Loss of ubiquitination at K225 (P = 0.0839);

MVP

0.70

MPC

0.051

ClinPred

0.64

GERP RS

-8.3

Varity_R

0.22

gMVP

0.76

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over