6-167136379-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_031409.4(CCR6):c.149C>T(p.Pro50Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00000547 in 1,461,862 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. P50P) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000055 (0 hom.)
• Consequence: CCR6 NM_031409.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.20

Genes affected

CCR6 (HGNC:1607): (C-C motif chemokine receptor 6) This gene encodes a member of the beta chemokine receptor family, which is predicted to be a seven transmembrane protein similar to G protein-coupled receptors. The gene is preferentially expressed by immature dendritic cells and memory T cells. The ligand of this receptor is macrophage inflammatory protein 3 alpha (MIP-3 alpha). This receptor has been shown to be important for B-lineage maturation and antigen-driven B-cell differentiation, and it may regulate the migration and recruitment of dentritic and T cells during inflammatory and immunological responses. Alternatively spliced transcript variants that encode the same protein have been described for this gene. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.94

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CCR6	NM_031409.4	c.149C>T	p.Pro50Leu	missense_variant	3/3	ENST00000341935.10
CCR6	NM_001394582.1	c.149C>T	p.Pro50Leu	missense_variant	4/4
CCR6	NM_004367.6	c.149C>T	p.Pro50Leu	missense_variant	3/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CCR6	ENST00000341935.10	c.149C>T	p.Pro50Leu	missense_variant	3/3	1	NM_031409.4	P1
CCR6	ENST00000349984.6	c.149C>T	p.Pro50Leu	missense_variant	4/4	1		P1
CCR6	ENST00000400926.5	c.149C>T	p.Pro50Leu	missense_variant	3/3	2		P1
CCR6	ENST00000643861.1	c.149C>T	p.Pro50Leu	missense_variant	4/4			P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251208 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135754

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000547 AC: 8 AN: 1461862 Hom.: 0 Cov.: 34 AF XY: 0.00000413 AC XY: 3 AN XY: 727232

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.0000374

Gnomad4 NFE exome AF: 0.00000270

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.0000113

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

Feb 16, 2023

The c.149C>T (p.P50L) alteration is located in exon 3 (coding exon 2) of the CCR6 gene. This alteration results from a C to T substitution at nucleotide position 149, causing the proline (P) at amino acid position 50 to be replaced by a leucine (L). 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	Pathogenic	0.87
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Uncertain	-0.080
Cadd	Uncertain	24
Dann	Uncertain	0.99
Eigen	Uncertain	0.31
Eigen_PC	Benign	0.17
FATHMM_MKL	Benign	0.69	D
LIST_S2	Benign	0.81	T;T;.;.;.
M_CAP	Benign	0.024	T
MetaRNN	Pathogenic	0.94	D;D;D;D;D
MetaSVM	Benign	-0.90	T
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.58	T
Polyphen		0.99	.;D;D;D;D
Vest4		0.66, 0.66, 0.66
MutPred		0.75		Loss of helix (P = 0.2271);Loss of helix (P = 0.2271);Loss of helix (P = 0.2271);Loss of helix (P = 0.2271);Loss of helix (P = 0.2271);
MVP		0.76
MPC		1.5
ClinPred		0.94	D
GERP RS		4.7
Varity_R		0.36
gMVP		0.71

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: rs1224171378; hg19: chr6-167549867; COSMIC: COSV59473836; COSMIC: COSV59473836;