chr12-8465555-G-A

Variant names:

• chr12-8465555-G-A
• rs749657245
• NM_001007033.2:c.295G>A
• CLEC6A p.Val99Ile

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_001007033.2(CLEC6A):c.295G>A (p.Val99Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a cumulative frequency of 0.000000684 (AC=1) in the gnomAD database across 1,461,792 control chromosomes (no homozygotes observed). The grpmax filtering allele frequency (95% CI) is 0.0000655. Note: a gnomAD entry for this variant shows a statistical allele-bias signature, consistent with mosaic/somatic contamination (e.g. age-related clonal hematopoiesis) rather than true inherited population frequency — this frequency should not be read as evidence of a common, benign germline variant. In-silico predictor (REVEL) classifies this variant as likely benign. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Other variants at the same amino acid position have been reported in ClinVar (not pathogenic): p.V99A: Uncertain_significance (ClinVar VariationId 4229804, 1 star); p.V99F: Likely_benign (ClinVar VariationId 2623059, 1 star)

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: CLEC6A NM_001007033.2 missense
• Clinical Significance: Not reported in ClinVar
• 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 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 = 0.0000655 — 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_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>A p.Val99Ile	missense	Exon 4 of 6	Prot: NP_001007034.1 UniProt:
	CLEC6A NM_001317999.2		c.205G>A p.Val69Ile	missense	Exon 3 of 5	Prot: NP_001304928.1 UniProt:

CLEC6A NM_001007033.2

MANE Select

HGVSc / HGVSpc.295G>Ap.Val99Ile

Exon rankExon 4 of 6

missense

Prot: NP_001007034.1UniProt: Q6EIG7-1

CLEC6A NM_001317999.2

HGVSc / HGVSpc.205G>Ap.Val69Ile

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>A p.Val99Ile	missense	Exon 4 of 6	Prot: ENSP00000371505.3 UniProt:

CLEC6A ENST00000382073.4

TSL:1MANE Select

HGVSc / HGVSpc.295G>Ap.Val99Ile

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 4 sources Large-scale international reference populations
GnomAD3 genomes	AF: 0.00000657	AC:1	Hom:0	AN:152104	Cov:32
GnomAD4 exome	AF: 6.84e-7	AC:1	Hom:0	AN:1461792	Cov:31
GnomAD4 genome Warning	AF: 0.00000657	AC:1	Hom:0	AN:152104	Cov:32
ALFA (dbGaP/dbSNP Allele Frequency Aggregator)	AF: 0.00	AC:0	Hom:0	AN:16840	Cov:

Showing 4 sources

Case/control cohorts

Cohort	Cases			Controls
	AF	AC	AN	AF	AC	AN
SCHEMA(Schizophrenia)	0.0000206	1	48450	0.00	0	74566

Showing 1 cohortAllele count / allele number. AF is computed from the counts for ASC (not provided by the source).

ClinVar

Not reported in ClinVar

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Benign	9.7
AlphaMissense	Benign	0.078
BayesDel_addAF	Benign	-0.41	T
BayesDel_noAF	Benign	-0.82
CADD	Benign	0.0040
DANN	Benign	0.76
DEOGEN2	Benign	0.030	T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.0033	N
FuncVEP CTI	Benign	0.079
GPN-Star LLR	N/A	-0.64
GPN-Star score	N/A	0.64
LIST_S2	Benign	0.34	T
M_CAP	Benign	0.0011	T
MetaRNN	Benign	0.15	T
MetaSVM	Benign	-0.98	T
Mutation Taster	N/A	100/0	polymorphism
MutationAssessor	Benign	-0.46	N
PhyloP100	Benign	-4.8
popEVE	Benign	-2.9
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-0.20	N
REVEL	Benign	0.018
Sift	Benign	0.27	T
Sift4G	Benign	0.069	T
Varity_R	N/A	0.054
VESM-3B	Benign	-2.3

Showing 28 of 28 scores

Splicing Scores

Algorithm	Calibrated pred.	Score	Prediction
Pangolin (max)	Benign	0.030
SpliceAI score (max)	Benign	0.060	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