19-8056208-C-T

Position:

• chr19-8056208-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_005624.4(CCL25):​c.130C>T​(p.Arg44Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00224 in 1,555,054 control chromosomes in the GnomAD database, including 56 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R44Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.010 (27 hom., cov: 30)
  • Exomes 𝑓: 0.0014 (29 hom.)
• Consequence: CCL25 NM_005624.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.463

Genes affected

CCL25 (HGNC:10624): (C-C motif chemokine ligand 25) This antimicrobial gene belongs to the subfamily of small cytokine CC genes. 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 dendritic cells, thymocytes, and activated macrophages but is inactive on peripheral blood lymphocytes and neutrophils. The product of this gene binds to chemokine receptor CCR9. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Sep 2014]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.00421229).
• BP6: Variant 19-8056208-C-T is Benign according to our data. Variant chr19-8056208-C-T is described in ClinVar as [Benign]. Clinvar id is 782620.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0105 (1535/146502) while in subpopulation AFR AF= 0.0352 (1411/40064). AF 95% confidence interval is 0.0337. There are 27 homozygotes in gnomad4. There are 703 alleles in male gnomad4 subpopulation. Median coverage is 30. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 27 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CCL25	NM_005624.4	c.130C>T	p.Arg44Trp	missense_variant	3/6	ENST00000315626.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CCL25	ENST00000315626.6	c.130C>T	p.Arg44Trp	missense_variant	3/6	2	NM_005624.4	A1

Frequencies

GnomAD3 genomes AF: 0.0105 AC: 1533 AN: 146394 Hom.: 27 Cov.: 30

Gnomad AFR AF: 0.0353

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00478

Gnomad ASJ AF: 0.000587

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000222

Gnomad FIN AF: 0.000105

Gnomad MID AF: 0.00325

Gnomad NFE AF: 0.000419

Gnomad OTH AF: 0.0113

GnomAD3 exomes AF: 0.00326 AC: 702 AN: 215490 Hom.: 12 AF XY: 0.00249 AC XY: 289 AN XY: 115936

Gnomad AFR exome AF: 0.0354

Gnomad AMR exome AF: 0.00325

Gnomad ASJ exome AF: 0.000994

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000128

Gnomad FIN exome AF: 0.000102

Gnomad NFE exome AF: 0.000394

Gnomad OTH exome AF: 0.00411

GnomAD4 exome AF: 0.00138 AC: 1950 AN: 1408552 Hom.: 29 Cov.: 32 AF XY: 0.00130 AC XY: 903 AN XY: 695976

Gnomad4 AFR exome AF: 0.0381

Gnomad4 AMR exome AF: 0.00336

Gnomad4 ASJ exome AF: 0.00161

Gnomad4 EAS exome AF: 0.0000260

Gnomad4 SAS exome AF: 0.0000631

Gnomad4 FIN exome AF: 0.000156

Gnomad4 NFE exome AF: 0.000319

Gnomad4 OTH exome AF: 0.00325

GnomAD4 genome AF: 0.0105 AC: 1535 AN: 146502 Hom.: 27 Cov.: 30 AF XY: 0.00988 AC XY: 703 AN XY: 71132

Gnomad4 AFR AF: 0.0352

Gnomad4 AMR AF: 0.00477

Gnomad4 ASJ AF: 0.000587

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000222

Gnomad4 FIN AF: 0.000105

Gnomad4 NFE AF: 0.000419

Gnomad4 OTH AF: 0.0112

Alfa AF: 0.00200 Hom.: 11

Bravo AF: 0.0115

TwinsUK AF: 0.00108 AC: 4

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.0334 AC: 141

ESP6500EA AF: 0.000355 AC: 3

ExAC AF: 0.00352 AC: 426

Asia WGS AF: 0.00231 AC: 8 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	May 31, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.29
BayesDel_addAF	Benign	-0.48	T
BayesDel_noAF	Benign	-0.44
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Benign	0.15	.;T;.
Eigen	Benign	-0.059
Eigen_PC	Benign	-0.34
FATHMM_MKL	Benign	0.029	N
LIST_S2	Benign	0.67	T;T;T
MetaRNN	Benign	0.0042	T;T;T
MetaSVM	Benign	-0.95	T
MutationAssessor	Pathogenic	3.2	M;M;.
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.27	T
PROVEAN	Pathogenic	-5.5	D;D;D
REVEL	Benign	0.072
Sift	Uncertain	0.0070	D;D;D
Sift4G	Uncertain	0.0030	D;D;D
Polyphen		1.0, 1.0	.;D;D
Vest4		0.43
MVP		0.73
MPC		1.1
ClinPred		0.061	T
GERP RS		2.8
Varity_R		0.24
gMVP		0.65

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: rs143413416; hg19: chr19-8121092;