12-10123309-G-A

Position:

• chr12-10123309-G-A

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_197947.3(CLEC7A):​c.547C>T​(p.Leu183Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00292 in 1,613,528 control chromosomes in the GnomAD database, including 26 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0034 (3 hom., cov: 31)
  • Exomes 𝑓: 0.0029 (23 hom.)
• Consequence: CLEC7A NM_197947.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 1.90

Genes affected

CLEC7A (HGNC:14558): (C-type lectin domain containing 7A) This gene encodes a member of the C-type lectin/C-type lectin-like domain (CTL/CTLD) superfamily. The encoded glycoprotein is a small type II membrane receptor with an extracellular C-type lectin-like domain fold and a cytoplasmic domain with an immunoreceptor tyrosine-based activation motif. It functions as a pattern-recognition receptor that recognizes a variety of beta-1,3-linked and beta-1,6-linked glucans from fungi and plants, and in this way plays a role in innate immune response. Alternate transcriptional splice variants, encoding different isoforms, have been characterized. This gene is closely linked to other CTL/CTLD superfamily members on chromosome 12p13 in the natural killer gene complex region. [provided by RefSeq, Jul 2008]

CLEC7A (HGNC:):

ACMG classification

Verdict is Benign. Variant got -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.015158027).
• BP6: Variant 12-10123309-G-A is Benign according to our data. Variant chr12-10123309-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 717363.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-10123309-G-A is described in Lovd as [Likely_benign].
• BS2: High Homozygotes in GnomAd4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CLEC7A	NM_197947.3	c.547C>T	p.Leu183Phe	missense_variant	5/6	ENST00000304084.13	NP_922938.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CLEC7A	ENST00000304084.13	c.547C>T	p.Leu183Phe	missense_variant	5/6	1	NM_197947.3	ENSP00000302569.8

Frequencies

GnomAD3 genomes AF: 0.00337 AC: 512 AN: 152012 Hom.: 3 Cov.: 31

Gnomad AFR AF: 0.000145

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000393

Gnomad ASJ AF: 0.00548

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0190

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00404

Gnomad OTH AF: 0.00239

GnomAD3 exomes AF: 0.00369 AC: 928 AN: 251466 Hom.: 2 AF XY: 0.00376 AC XY: 511 AN XY: 135908

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.0000867

Gnomad ASJ exome AF: 0.00764

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000327

Gnomad FIN exome AF: 0.0182

Gnomad NFE exome AF: 0.00369

Gnomad OTH exome AF: 0.00375

GnomAD4 exome AF: 0.00287 AC: 4194 AN: 1461398 Hom.: 23 Cov.: 29 AF XY: 0.00303 AC XY: 2201 AN XY: 727054

Gnomad4 AFR exome AF: 0.000179

Gnomad4 AMR exome AF: 0.000157

Gnomad4 ASJ exome AF: 0.00716

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000429

Gnomad4 FIN exome AF: 0.0168

Gnomad4 NFE exome AF: 0.00262

Gnomad4 OTH exome AF: 0.00245

GnomAD4 genome AF: 0.00337 AC: 512 AN: 152130 Hom.: 3 Cov.: 31 AF XY: 0.00390 AC XY: 290 AN XY: 74386

Gnomad4 AFR AF: 0.000145

Gnomad4 AMR AF: 0.000392

Gnomad4 ASJ AF: 0.00548

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0190

Gnomad4 NFE AF: 0.00404

Gnomad4 OTH AF: 0.00237

Alfa AF: 0.00358 Hom.: 2

Bravo AF: 0.00178

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00407 AC: 35

ExAC AF: 0.00367 AC: 446

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00311

EpiControl AF: 0.00231

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:5

Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Aug 08, 2018	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Dec 01, 2023	CLEC7A: BP4, BS2 -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.61
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Uncertain	-0.010
CADD	Uncertain	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.37	.;.;T
Eigen	Uncertain	0.68
Eigen_PC	Uncertain	0.56
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Uncertain	0.88	D;D;D
MetaRNN	Benign	0.015	T;T;T
MetaSVM	Benign	-0.61	T
MutationAssessor	Pathogenic	3.5	.;.;H
PrimateAI	Benign	0.38	T
PROVEAN	Uncertain	-3.4	D;D;D
REVEL	Benign	0.28
Sift	Pathogenic	0.0	D;D;D
Sift4G	Uncertain	0.0040	D;D;D
Polyphen		1.0	D;D;D
Vest4		0.75
MVP		0.37
MPC		0.23
ClinPred		0.13	T
GERP RS		4.3
Varity_R		0.87
gMVP		0.67

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs140318683; hg19: chr12-10275908; COSMIC: COSV53722382; COSMIC: COSV53722382;