18-321680-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1 PM2 PP3_Moderate

The NM_130386.3(COLEC12):c.2191G>A(p.Glu731Lys) variant causes a missense change. The variant allele was found at a frequency of 0.00000274 in 1,461,830 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: COLEC12 NM_130386.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.57

Genes affected

COLEC12 (HGNC:16016): (collectin subfamily member 12) This gene encodes a member of the C-lectin family, proteins that possess collagen-like sequences and carbohydrate recognition domains. This protein is a scavenger receptor that displays several functions associated with host defense. It can bind to carbohydrate antigens on microorganisms, facilitating their recognition and removal. It also mediates the recognition, internalization, and degradation of oxidatively modified low density lipoprotein by vascular endothelial cells. [provided by RefSeq, May 2018]

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM1: In a binding_site (size 0) in uniprot entity COL12_HUMAN
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.912

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COLEC12	NM_130386.3	c.2191G>A	p.Glu731Lys	missense_variant	9/10	ENST00000400256.5
COLEC12	XM_011525741.3	c.2140G>A	p.Glu714Lys	missense_variant	8/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COLEC12	ENST00000400256.5	c.2191G>A	p.Glu731Lys	missense_variant	9/10	1	NM_130386.3	P1
COLEC12	ENST00000582147.1	n.3997G>A		non_coding_transcript_exon_variant	8/9	5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461830 Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2 AN XY: 727216

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000282 Hom.: 0

Bravo AF: 0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 13, 2022

The c.2191G>A (p.E731K) alteration is located in exon 9 (coding exon 9) of the COLEC12 gene. This alteration results from a G to A substitution at nucleotide position 2191, causing the glutamic acid (E) at amino acid position 731 to be replaced by a lysine (K). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.38
BayesDel_addAF	Uncertain	0.028	T
BayesDel_noAF	Benign	-0.20
Cadd	Pathogenic	32
Dann	Pathogenic	1.0
DEOGEN2	Benign	0.029	T
Eigen	Pathogenic	0.69
Eigen_PC	Pathogenic	0.70
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.91	D
M_CAP	Benign	0.046	D
MetaRNN	Pathogenic	0.91	D
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.3	L
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.64	T
PROVEAN	Benign	-1.5	N
REVEL	Uncertain	0.31
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.0030	D
Polyphen		1.0	D
Vest4		0.67
MutPred		0.83		Gain of methylation at E731 (P = 9e-04);
MVP		0.27
MPC		0.88
ClinPred		0.95	D
GERP RS		5.7
Varity_R		0.92
gMVP		0.98

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs1404522800; hg19: chr18-321680; COSMIC: COSV101232126; COSMIC: COSV101232126;