rs17549193

Positions:

• chr9-134887180-C-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BA1

The NM_004108.3(FCN2):​c.707C>T​(p.Thr236Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.278 in 1,613,120 control chromosomes in the GnomAD database, including 64,243 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.29 (6900 hom., cov: 32)
  • Exomes 𝑓: 0.28 (57343 hom.)
• Consequence: FCN2 NM_004108.3 missense
• Clinical Significance: Benign no assertion criteria provided B:1
• Conservation: PhyloP100: -0.351

Genes affected

FCN2 (HGNC:3624): (ficolin 2) The product of this gene belongs to the ficolin family of proteins. This family is characterized by the presence of a leader peptide, a short N-terminal segment, followed by a collagen-like region, and a C-terminal fibrinogen-like domain. This gene is predominantly expressed in the liver, and has been shown to have carbohydrate binding and opsonic activities. Alternatively spliced transcript variants encoding different isoforms have been identified. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=4.5707822E-4).
• BP6: Variant 9-134887180-C-T is Benign according to our data. Variant chr9-134887180-C-T is described in ClinVar as [Benign]. Clinvar id is 3060333.Status of the report is no_assertion_criteria_provided, 0 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.342 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FCN2	NM_004108.3	c.707C>T	p.Thr236Met	missense_variant	8/8	ENST00000291744.11	NP_004099.2
FCN2	NM_015837.3	c.593C>T	p.Thr198Met	missense_variant	7/7		NP_056652.1
FCN2	XM_011518392.4	c.674C>T	p.Thr225Met	missense_variant	8/8		XP_011516694.1
FCN2	XM_006717015.5	c.560C>T	p.Thr187Met	missense_variant	7/7		XP_006717078.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FCN2	ENST00000291744.11	c.707C>T	p.Thr236Met	missense_variant	8/8	1	NM_004108.3	ENSP00000291744	P1
FCN2	ENST00000350339.3	c.593C>T	p.Thr198Met	missense_variant	7/7	5		ENSP00000291741

Frequencies

GnomAD3 genomes AF: 0.294 AC: 44728 AN: 152002 Hom.: 6888 Cov.: 32

Gnomad AFR AF: 0.346

Gnomad AMI AF: 0.599

Gnomad AMR AF: 0.246

Gnomad ASJ AF: 0.281

Gnomad EAS AF: 0.0651

Gnomad SAS AF: 0.280

Gnomad FIN AF: 0.284

Gnomad MID AF: 0.348

Gnomad NFE AF: 0.291

Gnomad OTH AF: 0.267

GnomAD3 exomes AF: 0.258 AC: 64816 AN: 251468 Hom.: 9036 AF XY: 0.259 AC XY: 35225 AN XY: 135912

Gnomad AFR exome AF: 0.345

Gnomad AMR exome AF: 0.199

Gnomad ASJ exome AF: 0.272

Gnomad EAS exome AF: 0.0554

Gnomad SAS exome AF: 0.272

Gnomad FIN exome AF: 0.278

Gnomad NFE exome AF: 0.287

Gnomad OTH exome AF: 0.263

GnomAD4 exome AF: 0.277 AC: 403986 AN: 1461000 Hom.: 57343 Cov.: 36 AF XY: 0.277 AC XY: 201639 AN XY: 726850

Gnomad4 AFR exome AF: 0.340

Gnomad4 AMR exome AF: 0.205

Gnomad4 ASJ exome AF: 0.270

Gnomad4 EAS exome AF: 0.0594

Gnomad4 SAS exome AF: 0.277

Gnomad4 FIN exome AF: 0.272

Gnomad4 NFE exome AF: 0.286

Gnomad4 OTH exome AF: 0.272

GnomAD4 genome AF: 0.294 AC: 44773 AN: 152120 Hom.: 6900 Cov.: 32 AF XY: 0.292 AC XY: 21680 AN XY: 74368

Gnomad4 AFR AF: 0.347

Gnomad4 AMR AF: 0.246

Gnomad4 ASJ AF: 0.281

Gnomad4 EAS AF: 0.0647

Gnomad4 SAS AF: 0.279

Gnomad4 FIN AF: 0.284

Gnomad4 NFE AF: 0.291

Gnomad4 OTH AF: 0.264

Alfa AF: 0.281 Hom.: 10086

Bravo AF: 0.289

TwinsUK AF: 0.279 AC: 1036

ALSPAC AF: 0.268 AC: 1033

ESP6500AA AF: 0.340 AC: 1500

ESP6500EA AF: 0.290 AC: 2495

ExAC AF: 0.262 AC: 31846

Asia WGS AF: 0.192 AC: 667 AN: 3478

EpiCase AF: 0.289

EpiControl AF: 0.286

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

Submissions by phenotype

FCN2-related disorder Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Nov 01, 2022

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.52	T
BayesDel_noAF	Benign	-0.37
CADD	Benign	11
DANN	Benign	0.95
DEOGEN2	Benign	0.025	T;.
Eigen	Benign	-0.48
Eigen_PC	Benign	-0.63
FATHMM_MKL	Benign	0.21	N
LIST_S2	Benign	0.83	T;T
MetaRNN	Benign	0.00046	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.6	M;.
MutationTaster	Benign	0.98	P;P
PrimateAI	Benign	0.33	T
PROVEAN	Uncertain	-2.9	D;D
REVEL	Benign	0.23
Sift	Uncertain	0.0050	D;D
Sift4G	Uncertain	0.047	D;T
Polyphen		0.57	P;P
Vest4		0.045
MPC		0.094
ClinPred		0.025	T
GERP RS		2.1
Varity_R		0.19
gMVP		0.42

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: rs17549193; hg19: chr9-137779026; COSMIC: COSV52475907;