NM_002993.4:c.32T>C

Variant names:

• chr4-73836782-T-C
• rs768103843
• NM_002993.4:c.32T>C
• CXCL6 p.Val11Ala

GermlineCancer (beta)

Variant summary

Our verdict is Uncertain significance.

0 Uncertain · Cold

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received 0 classification points (ACMG Germline Pathogenicity v2019). PM2BP4_Moderate

The NM_002993.4(CXCL6):c.32T>C (p.Val11Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a cumulative frequency of 0.0000161 (AC=26) in the gnomAD database across 1,611,560 control chromosomes (no homozygotes observed). The grpmax filtering allele frequency (95% CI) is 0.0000146. In-silico predictor (REVEL) classifies this variant as likely benign. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain Significance (★).

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000016 (0 hom.)
• Consequence: CXCL6 NM_002993.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.978
• Publications: 1 publications found

Genes affected

CXCL6 (HGNC:10643): (C-X-C motif chemokine ligand 6) The protein encoded by this gene is a member CXC chemokine family. The encoded protein is a chemotactic for neutrophil granulocytes and has antibacterial action against gram-negative and gram-positive bacteria. This gene and other members of the CXC chemokine gene family form a gene cluster in a region of chromosome 4q. [provided by RefSeq, Jun 2020]

ENSG00000298131 (HGNC:):

Classification according to ACMG Germline Pathogenicity v2019

Classification was made for transcript:

Our verdict: Uncertain_significance. The variant received 0 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	PM2Absent/extremely low in population databases		Very rare in gnomAD for AR/unknown gene (popmax AF < threshold/10) — PM2; GnomAD popmax AF = 0.0000146 — very rare for unknown gene (threshold 0.001) — PM2 moderate.
	BP4Computational evidence suggests no impact		Computational evidence supports benign — no pathogenic computational or splicing signal (BP4); Splicing verdict: benign (Strong).; Germline computational verdict: benign (Moderate).

Variant Effect in Transcripts

Automated classification analysis was done for transcript: NM_002993.4. You can select a different transcript below to see updated classification assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CXCL6	NM_002993.4	MANE Select	c.32T>C	p.Val11Ala	missense	Exon 1 of 4	NP_002984.1	P80162

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CXCL6	ENST00000226317.10	TSL:1 MANE Select	c.32T>C	p.Val11Ala	missense	Exon 1 of 4	ENSP00000226317.5	P80162
	CXCL6	ENST00000515050.1	TSL:1	c.32T>C	p.Val11Ala	missense	Exon 1 of 3	ENSP00000424819.1	D6RF92
	ENSG00000298131	ENST00000753200.1		n.196A>G		non_coding_transcript_exon	Exon 1 of 1

Frequencies

Allele frequencies (AF), counts (AC/AN), homozygotes and coverage

Common (AF > 0.05 / Hom > 5)

Rare (AF ≤ 0.0001 / Hom ≤ 1)

Source / population	AF	AC	Hom	AN	Coverage
Global population databases 6 sources Large-scale international reference populations
GnomAD3 genomes	AF: 0.0000131	AC:2	Hom:0	AN:152142	Cov:32
GnomAD2 exomes	AF: 0.00000408	AC:1	Hom:	AN:245036	Cov:
GnomAD4 exome	AF: 0.0000164	AC:24	Hom:0	AN:1459418	Cov:32
GnomAD4 genome	AF: 0.0000131	AC:2	Hom:0	AN:152142	Cov:32
TOPMed (Bravo)	AF: 0.0000189	AC:	Hom:	AN:	Cov:
ALFA (dbGaP/dbSNP Allele Frequency Aggregator)	AF: 0.00	AC:0	Hom:0	AN:16840	Cov:

Showing 6 sources

Case/control cohorts

Cohort	Cases			Controls
	AF	AC	AN	AF	AC	AN
BipEx(Bipolar disorder (including schizoaffective))	0.000106	3	28420	0.00	0	28844
Epi25(Epilepsy)	0.0000238	1	41958	0.00	0	66888
SCHEMA(Schizophrenia)	0.00000969	1	103152	0.00	0	184166

Showing 3 cohortsAllele count / allele number. AF is computed from the counts for ASC (not provided by the source).

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational Scores

Algorithm	Calibrated prediction	Prediction	Score
AlphaGenome AVI	Benign	-	0.90
AlphaMissense	Benign	-	0.11
BayesDel_addAF	Benign	T	-0.35
BayesDel_noAF	Benign	-	-0.74
CADD	Benign	-	0.59
DANN	Benign	-	0.40
DEOGEN2	Benign	T	0.045
Eigen	Benign	-	-1.5
Eigen_PC	Benign	-	-1.6
FATHMM_MKL	Benign	N	0.031
FuncVEP CTI	Benign	-	0.026
GPN-Star LLR	N/A	-	-1.0
GPN-Star score	N/A	-	1.0
LIST_S2	Benign	T	0.43
M_CAP	Benign	T	0.0054
MetaRNN	Benign	T	0.052
MetaSVM	Benign	T	-1.0
Mutation Taster	N/A	polymorphism	97/3
MutationAssessor	Benign	L	1.8
PhyloP100	Benign	-	-0.98
popEVE	Benign	-	-2.4
PrimateAI	Uncertain	T	0.53
PromoterAI	N/A	Neutral	-0.0092
PROVEAN	Benign	N	0.060
REVEL	Benign	-	0.036
Sift	Uncertain	D	0.013
Sift4G	Benign	T	0.66
Varity_R	N/A	-	0.044
VESM-3B	Benign	-	-1.6

Showing 29 of 29 scores

Splicing Scores

Algorithm	Calibrated prediction	Prediction	Score
Pangolin (max)	Benign	-	0.0
SpliceAI score (max)	Benign	- Details are displayed if max score is > 0.2	0.0

Showing 2 of 2 scores

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs768103843;

hg19: chr4-74702499;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar