chr12-8465555-G-T

Variant names:

• chr12-8465555-G-T
• rs749657245
• NM_001007033.2:c.295G>T
• CLEC6A p.Val99Phe

GermlineCancer (beta)

Variant summary

Our verdict is Likely benign.

-1 Likely Benign

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received -1 classification points (ACGS-UK Somatic Oncogenicity v2025). B3_Supporting

The NM_001007033.2(CLEC6A):c.295G>T (p.Val99Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a cumulative frequency of 0.00000496 (AC=8) in the gnomAD database across 1,613,896 control chromosomes (no homozygotes observed). The grpmax filtering allele frequency (95% CI) is 0.000193. 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 Benign/Likely Benign (★). Other variants at the same amino acid position have been reported in ClinVar (not pathogenic): p.V99A: Uncertain_significance (ClinVar VariationId 4229804, 1 star)

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000048 (0 hom.)
• Consequence: CLEC6A NM_001007033.2 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -4.85
• Publications: 0 publications found

Genes affected

CLEC6A (HGNC:14556): (C-type lectin domain containing 6A) The protein encoded by this gene is a type II membrane receptor with an extracellular C-type lectin-like domain fold. The extracellular portion binds structures with a high mannose content and has been shown to recognize several pathogens, including C. elegans, S. cerevisiae, M. tuberculosis, C. neoformans, and house dust mite. When stimulated, the encoded protein initiates signalling through the CARD9-Bcl10-Malt1 pathway, leading to the induction of cytokines. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Dec 2015]

Classification according to ACGS-UK Somatic Oncogenicity v2025

Classification was made for transcript:

Our verdict: Likely_benign. The variant received -1 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	B3Computational evidence does not support deleterious effect		Computational evidence does not support a deleterious effect; Missense variant — primary computational scorer does not support an oncogenic/deleterious effect; supports B3

Variant Effect in Transcripts

Automated classification analysis was done for transcript: NM_001007033.2. 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
	CLEC6A NM_001007033.2	MANE Select	c.295G>T p.Val99Phe	missense	Exon 4 of 6	Prot: NP_001007034.1 UniProt:
	CLEC6A NM_001317999.2		c.205G>T p.Val69Phe	missense	Exon 3 of 5	Prot: NP_001304928.1 UniProt:

CLEC6A NM_001007033.2

MANE Select

HGVSc / HGVSpc.295G>Tp.Val99Phe

Exon rankExon 4 of 6

missense

Prot: NP_001007034.1UniProt: Q6EIG7-1

CLEC6A NM_001317999.2

HGVSc / HGVSpc.205G>Tp.Val69Phe

Exon rankExon 3 of 5

missense

Prot: NP_001304928.1UniProt: Q6EIG7-2

Ensembl Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	CLEC6A ENST00000382073.4	TSL:1MANE Select	c.295G>T p.Val99Phe	missense	Exon 4 of 6	Prot: ENSP00000371505.3 UniProt:

CLEC6A ENST00000382073.4

TSL:1MANE Select

HGVSc / HGVSpc.295G>Tp.Val99Phe

Exon rankExon 4 of 6

missense

Prot: ENSP00000371505.3UniProt: Q6EIG7-1

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: 0.00000657	AC:1	Hom:0	AN:152104	Cov:32
GnomAD2 exomes	AF: 0.00000796	AC:2	Hom:	AN:251412	Cov:
GnomAD4 exome	AF: 0.00000479	AC:7	Hom:0	AN:1461792	Cov:31
GnomAD4 genome	AF: 0.00000657	AC:1	Hom:0	AN:152104	Cov:32
TOPMed (Bravo)	AF: 0.0000113	AC:3	Hom:0	AN:264690	Cov:
ALFA (dbGaP/dbSNP Allele Frequency Aggregator)	AF: 0.00	AC:0	Hom:0	AN:16840	Cov:
Local & regional cohorts 1 source Population-specific and national genomic databases
WBBC (Westlake BioBank for Chinese) pilot	AF: 0.000112	AC:1	Hom:0	AN:8960	Cov:

Showing 7 sources

Case/control cohorts

Cohort	Cases			Controls
	AF	AC	AN	AF	AC	AN
ASC(Autism)	0.000104 *	1	9620	0.00 *	0	10426
SCHEMA(Schizophrenia)	0.0000193	2	103376	0.0000108	2	184672

Showing 2 cohortsAllele count / allele number. AF is computed from the counts for ASC (not provided by the source).

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

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

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Benign	5.6
AlphaMissense	Benign	0.063
BayesDel_addAF	Benign	-0.56	T
BayesDel_noAF	Benign	-0.81
CADD	Benign	0.0040
DANN	Benign	0.76
DEOGEN2	Benign	0.030	T
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.0022	N
FuncVEP CTI	Benign	0.0093
GPN-Star LLR	N/A	1.1
GPN-Star score	N/A	-1.1
LIST_S2	Benign	0.34	T
M_CAP	Benign	0.0014	T
MetaRNN	Benign	0.12	T
MetaSVM	Benign	-0.98	T
Mutation Taster	N/A	98/2	polymorphism
MutationAssessor	Benign	-1.3	N
PhyloP100	Benign	-4.8
popEVE	Benign	-2.8
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-0.32	N
REVEL	Benign	0.013
Sift	Benign	0.21	T
Sift4G	Benign	0.15	T
Varity_R	N/A	0.067
VESM-3B	Benign	-4.6

Showing 28 of 28 scores

Splicing Scores

Algorithm	Calibrated pred.	Score	Prediction
Pangolin (max)	Benign	0.010
SpliceAI score (max)	Benign	0.020	Details are displayed if max score is > 0.2

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.

MaveDB functional evidence

MaveDB is a public repository of laboratory assays that test the effect of thousands of variants at once — treat this as supporting research data and interpret it with great caution; it is not a clinical classification.

No MaveDB functional evidence found for this variant.

Other links and lift over

dbSNP: rs749657245;

hg19: chr12-8618151;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar