16-57360506-G-A

Variant summary

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

The NM_002990.5(CCL22):c.143G>A(p.Arg48His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000143 in 1,614,114 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R48C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000046 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00015 (0 hom.)
• Consequence: CCL22 NM_002990.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.79

Genes affected

CCL22 (HGNC:10621): (C-C motif chemokine ligand 22) This antimicrobial gene is one of several Cys-Cys (CC) cytokine genes clustered on the q arm of chromosome 16. Cytokines are a family of secreted proteins involved in immunoregulatory and inflammatory processes. The CC cytokines are proteins characterized by two adjacent cysteines. The cytokine encoded by this gene displays chemotactic activity for monocytes, dendritic cells, natural killer cells and for chronically activated T lymphocytes. It also displays a mild activity for primary activated T lymphocytes and has no chemoattractant activity for neutrophils, eosinophils and resting T lymphocytes. The product of this gene binds to chemokine receptor CCR4. This chemokine may play a role in the trafficking of activated T lymphocytes to inflammatory sites and other aspects of activated T lymphocyte physiology. [provided by RefSeq, Sep 2014]

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=0.38093507).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CCL22	NM_002990.5	c.143G>A	p.Arg48His	missense_variant	2/3	ENST00000219235.5
CCL22	XM_047434449.1	c.182G>A	p.Arg61His	missense_variant	3/4
CCL22	XM_047434450.1	c.143G>A	p.Arg48His	missense_variant	3/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CCL22	ENST00000219235.5	c.143G>A	p.Arg48His	missense_variant	2/3	1	NM_002990.5	P1

Frequencies

GnomAD3 genomes AF: 0.0000460 AC: 7 AN: 152248 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000482

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000676 AC: 17 AN: 251468 Hom.: 0 AF XY: 0.0000809 AC XY: 11 AN XY: 135908

Gnomad AFR exome AF: 0.000246

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.0000992

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.000139

Gnomad NFE exome AF: 0.0000703

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000153 AC: 224 AN: 1461866 Hom.: 0 Cov.: 32 AF XY: 0.000131 AC XY: 95 AN XY: 727232

Gnomad4 AFR exome AF: 0.0000597

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.000112

Gnomad4 NFE exome AF: 0.000184

Gnomad4 OTH exome AF: 0.000132

GnomAD4 genome AF: 0.0000460 AC: 7 AN: 152248 Hom.: 0 Cov.: 33 AF XY: 0.0000672 AC XY: 5 AN XY: 74382

Gnomad4 AFR AF: 0.0000482

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000588

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000150 Hom.: 0

Bravo AF: 0.0000718

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.0000577 AC: 7

EpiCase AF: 0.0000545

EpiControl AF: 0.000119

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

Sep 07, 2022

The c.143G>A (p.R48H) alteration is located in exon 2 (coding exon 2) of the CCL22 gene. This alteration results from a G to A substitution at nucleotide position 143, causing the arginine (R) at amino acid position 48 to be replaced by a histidine (H). 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	0.13
BayesDel_addAF	Benign	-0.43	T
BayesDel_noAF	Benign	-0.56
Cadd	Benign	21
Dann	Uncertain	1.0
DEOGEN2	Benign	0.016	T
Eigen	Benign	-0.27
Eigen_PC	Benign	-0.51
FATHMM_MKL	Benign	0.086	N
LIST_S2	Benign	0.59	T
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.38	T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.39	T
PROVEAN	Uncertain	-2.4	N
REVEL	Benign	0.053
Sift	Uncertain	0.018	D
Sift4G	Uncertain	0.031	D
Polyphen		1.0	D
Vest4		0.46
MVP		0.20
MPC		1.2
ClinPred		0.35	T
GERP RS		0.81
Varity_R		0.060
gMVP		0.59

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: rs376546990; hg19: chr16-57394418; COSMIC: COSV99536567;