CLEC6A p.Val99Phe

Variant names:

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

Your query was ambiguous. Multiple possible variants found:

• chr12-8465555-G-T
• chr12-8465555-GTT-TTC

GermlineCancer (beta)

Variant summary

Our verdict is Likely benign.

-5 Likely Benign

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received -5 classification points (ACMG Germline Pathogenicity v2019). PM2_SupportingBP4_StrongBP6_Moderate

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 ACMG Germline Pathogenicity v2019

Our verdict: Likely_benign. The variant received -5 points.

• PM2: Rare in gnomAD for AR/unknown gene (popmax AF below threshold) — PM2 Supporting; GnomAD popmax AF = 0.000193 — borderline rare for unknown gene (threshold 0.001) — PM2 supporting.
• BP4: Computational evidence supports benign — no pathogenic computational or splicing signal (BP4); Splicing verdict: benign (Strong).; Germline computational verdict: benign (Strong).
• BP6: ClinVar 1-star benign — moderate (BP6); ClinVar germline classification: Benign/Likely Benign, 1 star(s).

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	NP_001007034.1	Q6EIG7-1
	CLEC6A	NM_001317999.2		c.205G>T	p.Val69Phe	missense	Exon 3 of 5	NP_001304928.1	Q6EIG7-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CLEC6A	ENST00000382073.4	TSL:1 MANE Select	c.295G>T	p.Val99Phe	missense	Exon 4 of 6	ENSP00000371505.3	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	0.00000657	1	0	152104	32
GnomAD2 exomes	0.00000796	2		251412
GnomAD4 exome	0.00000479	7	0	1461792	31
GnomAD4 genome	0.00000657	1	0	152104	32
TOPMed (Bravo)	0.0000113	3	0	264690
ALFA (dbGaP/dbSNP Allele Frequency Aggregator)	0.00	0	0	16840
Local & regional cohorts 1 source Population-specific and national genomic databases
WBBC (Westlake BioBank for Chinese) pilot	0.000112	1	0	8960

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

Showing 28 of 28 scores

Splicing Scores

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

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: rs749657245;

hg19: chr12-8618151;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar