6-167137266-T-C

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_031409.4(CCR6):c.1036T>C(p.Phe346Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: CCR6 NM_031409.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.29

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_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.047987014).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CCR6	NM_031409.4	c.1036T>C	p.Phe346Leu	missense_variant	3/3	ENST00000341935.10
CCR6	NM_001394582.1	c.1036T>C	p.Phe346Leu	missense_variant	4/4
CCR6	NM_004367.6	c.1036T>C	p.Phe346Leu	missense_variant	3/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CCR6	ENST00000341935.10	c.1036T>C	p.Phe346Leu	missense_variant	3/3	1	NM_031409.4	P1
CCR6	ENST00000349984.6	c.1036T>C	p.Phe346Leu	missense_variant	4/4	1		P1
CCR6	ENST00000400926.5	c.1036T>C	p.Phe346Leu	missense_variant	3/3	2		P1
CCR6	ENST00000643861.1	c.1036T>C	p.Phe346Leu	missense_variant	4/4			P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 33

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

Oct 26, 2022

The c.1036T>C (p.F346L) alteration is located in exon 3 (coding exon 2) of the CCR6 gene. This alteration results from a T to C substitution at nucleotide position 1036, causing the phenylalanine (F) at amino acid position 346 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	Uncertain	0.38
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.58
Cadd	Benign	3.8
Dann	Benign	0.46
DEOGEN2	Benign	0.056	T;T;T;T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.068	N
LIST_S2	Benign	0.35	T;.;.;.
M_CAP	Benign	0.0052	T
MetaRNN	Benign	0.048	T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.32	N;N;N;N
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-0.46	N;.;N;N
REVEL	Benign	0.039
Sift	Benign	0.71	T;.;T;T
Sift4G	Benign	0.67	T;.;T;T
Polyphen		0.0	B;B;B;B
Vest4		0.037
MutPred		0.29		Loss of methylation at K342 (P = 0.0933);Loss of methylation at K342 (P = 0.0933);Loss of methylation at K342 (P = 0.0933);Loss of methylation at K342 (P = 0.0933);
MVP		0.38
MPC		0.69
ClinPred		0.032	T
GERP RS		-0.19
Varity_R		0.042
gMVP		0.27

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: rs1583003329; hg19: chr6-167550754;