CLEC6A p.Ser94Phe

Variant names:

• chr12-8465541-C-T
• rs1349488194
• NM_001007033.2:c.281C>T
• CLEC6A p.Ser94Phe

Your query was ambiguous. Multiple possible variants found:

• chr12-8465541-C-T
• chr12-8465541-CC-TT

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.281C>T (p.Ser94Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a cumulative frequency of 0.00000434 (AC=7) in the gnomAD database across 1,613,526 control chromosomes (no homozygotes observed). The grpmax filtering allele frequency (95% CI) is 0.0000325. 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 0.000026 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: CLEC6A NM_001007033.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.584
• 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 = 0.0000325 — 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.281C>T p.Ser94Phe	missense	Exon 4 of 6	Prot: NP_001007034.1 UniProt:
	CLEC6A NM_001317999.2		c.191C>T p.Ser64Phe	missense	Exon 3 of 5	Prot: NP_001304928.1 UniProt:

CLEC6A NM_001007033.2

MANE Select

HGVSc / HGVSpc.281C>Tp.Ser94Phe

Exon rankExon 4 of 6

missense

Prot: NP_001007034.1UniProt: Q6EIG7-1

CLEC6A NM_001317999.2

HGVSc / HGVSpc.191C>Tp.Ser64Phe

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.281C>T p.Ser94Phe	missense	Exon 4 of 6	Prot: ENSP00000371505.3 UniProt:

CLEC6A ENST00000382073.4

TSL:1MANE Select

HGVSc / HGVSpc.281C>Tp.Ser94Phe

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: 0.0000263	AC:4	Hom:0	AN:152012	Cov:32
GnomAD2 exomes	AF: 0.00000398	AC:1	Hom:	AN:251410	Cov:
GnomAD4 exome	AF: 0.00000205	AC:3	Hom:0	AN:1461514	Cov:31
GnomAD4 genome	AF: 0.0000263	AC:4	Hom:0	AN:152012	Cov:32
TOPMed (Bravo)	AF: 0.00000756	AC:2	Hom:0	AN:264690	Cov:
ALFA (dbGaP/dbSNP Allele Frequency Aggregator)	AF: 0.0000262	AC:1	Hom:0	AN:38218	Cov:

Showing 6 sources

Case/control cohorts

Cohort	Cases			Controls
	AF	AC	AN	AF	AC	AN
SCHEMA(Schizophrenia)	0.0000172	1	58220	0.0000248	2	80532

Showing 1 cohortAllele 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 pred.	Score	Prediction
AlphaGenome AVI	Pathogenic	21
AlphaMissense	Uncertain	0.37
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Benign	-0.45
CADD	Benign	20
DANN	Uncertain	0.99
DEOGEN2	Benign	0.39	T
Eigen	Benign	-0.28
Eigen_PC	Benign	-0.42
FATHMM_MKL	Benign	0.039	N
FuncVEP CTI	Pathogenic	0.85
GPN-Star LLR	N/A	-3.7
GPN-Star score	N/A	3.7
LIST_S2	Benign	0.52	T
M_CAP	Benign	0.0016	T
MetaRNN	Benign	0.33	T
MetaSVM	Benign	-1.1	T
Mutation Taster	N/A	70/30	polymorphism
MutationAssessor	Uncertain	2.1	M
PhyloP100	Benign	0.58
popEVE	Benign	-3.6
PrimateAI	Benign	0.31	T
PROVEAN	Uncertain	-3.7	D
REVEL	Benign	0.12
Sift	Uncertain	0.024	D
Sift4G	Uncertain	0.030	D
Varity_R	N/A	0.38
VESM-3B	Benign	-8.6

Showing 28 of 28 scores

Splicing Scores

Algorithm	Calibrated pred.	Score	Prediction
Pangolin (max)	Benign	0.060
SpliceAI score (max)	Benign	0.010	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: rs1349488194;

hg19: chr12-8618137;

COSMIC: COSV65988182;

COSMIC: COSV65988182;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar