Genetic Variant NM_004108.3:c.772G>T (chr9-134887245-G-T) – ACMG Classification: Benign (-9 pts)

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP6BA1

The NM_004108.3(FCN2):c.772G>T(p.Ala258Ser) variant causes a missense change. The variant allele was found at a frequency of 0.117 in 1,614,000 control chromosomes in the GnomAD database, including 11,750 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in UniProt.

Frequency

Genomes: 𝑓 0.13 ( 1456 hom., cov: 33)

Exomes 𝑓: 0.12 ( 10294 hom. )

Consequence

FCN2
NM_004108.3 missense

Scores

Clinical Significance

Benign no assertion criteria provided B:1

Conservation

PhyloP100: 6.35

Variant links:

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]

FCN2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -9 ACMG points.

BP6

Variant 9-134887245-G-T is Benign according to our data. Variant chr9-134887245-G-T is described in ClinVar as [Benign]. Clinvar id is 3059902.Status of the report is no_assertion_criteria_provided, 0 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.19 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FCN2	NM_004108.3 link	c.772G>T	p.Ala258Ser	missense_variant	Exon 8 of 8	ENST00000291744.11	NP_004099.2	Q15485-1
FCN2	NM_015837.3 link	c.658G>T	p.Ala220Ser	missense_variant	Exon 7 of 7		NP_056652.1	Q15485-2
FCN2	XM_011518392.4 link	c.739G>T	p.Ala247Ser	missense_variant	Exon 8 of 8		XP_011516694.1
FCN2	XM_006717015.5 link	c.625G>T	p.Ala209Ser	missense_variant	Exon 7 of 7		XP_006717078.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FCN2	ENST00000291744.11 link	c.772G>T	p.Ala258Ser	missense_variant	Exon 8 of 8	1	NM_004108.3	ENSP00000291744.6		Q15485-1
FCN2	ENST00000350339.3 link	c.658G>T	p.Ala220Ser	missense_variant	Exon 7 of 7	5		ENSP00000291741.5		Q15485-2

Frequencies

GnomAD3 genomes

AF:

0.135

AC:

20474

AN:

152124

Hom.:

1456

Cov.:

show subpopulations

Gnomad AFR

AF:

0.194

Gnomad AMI

AF:

0.0208

Gnomad AMR

AF:

0.126

Gnomad ASJ

AF:

0.0418

Gnomad EAS

AF:

0.177

Gnomad SAS

AF:

0.122

Gnomad FIN

AF:

0.0950

Gnomad MID

AF:

0.0316

Gnomad NFE

AF:

0.111

Gnomad OTH

AF:

0.129

GnomAD3 exomes

AF:

0.125

AC:

31345

AN:

251484

Hom.:

2226

AF XY:

0.123

AC XY:

16655

AN XY:

135916

show subpopulations

Gnomad AFR exome

AF:

0.196

Gnomad AMR exome

AF:

0.146

Gnomad ASJ exome

AF:

0.0499

Gnomad EAS exome

AF:

0.177

Gnomad SAS exome

AF:

0.128

Gnomad FIN exome

AF:

0.102

Gnomad NFE exome

AF:

0.110

Gnomad OTH exome

AF:

0.114

GnomAD4 exome

AF:

0.115

AC:

168439

AN:

1461758

Hom.:

10294

Cov.:

AF XY:

0.115

AC XY:

83401

AN XY:

727180

show subpopulations

Gnomad4 AFR exome

AF:

0.199

Gnomad4 AMR exome

AF:

0.145

Gnomad4 ASJ exome

AF:

0.0469

Gnomad4 EAS exome

AF:

0.158

Gnomad4 SAS exome

AF:

0.123

Gnomad4 FIN exome

AF:

0.104

Gnomad4 NFE exome

AF:

0.112

Gnomad4 OTH exome

AF:

0.112

GnomAD4 genome

AF:

0.135

AC:

20497

AN:

152242

Hom.:

1456

Cov.:

AF XY:

0.133

AC XY:

9896

AN XY:

74438

show subpopulations

Gnomad4 AFR

AF:

0.194

Gnomad4 AMR

AF:

0.126

Gnomad4 ASJ

AF:

0.0418

Gnomad4 EAS

AF:

0.178

Gnomad4 SAS

AF:

0.122

Gnomad4 FIN

AF:

0.0950

Gnomad4 NFE

AF:

0.111

Gnomad4 OTH

AF:

0.130

Alfa

AF:

0.113

Hom.:

2558

Bravo

AF:

0.141

TwinsUK

AF:

0.114

AC:

423

ALSPAC

AF:

0.116

AC:

448

ESP6500AA

AF:

0.193

AC:

850

ESP6500EA

AF:

0.107

AC:

919

ExAC

AF:

0.125

AC:

15165

Asia WGS

AF:

0.154

AC:

540

AN:

3478

EpiCase

AF:

0.102

EpiControl

AF:

0.102

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

FCN2-related disorder

Benign:1

Nov 02, 2022

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

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

0.16

BayesDel_addAF

Benign

-0.43

BayesDel_noAF

Benign

-0.25

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Benign

0.090

T;.

Eigen

Uncertain

0.36

Eigen_PC

Benign

0.18

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Benign

0.81

T;T

MetaRNN

Benign

0.0026

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Uncertain

2.2

M;.

PrimateAI

Benign

0.43

PROVEAN

Uncertain

-2.7

D;D

REVEL

Uncertain

0.47

Sift

Uncertain

0.022

D;D

Sift4G

Uncertain

0.014

D;D

Polyphen

0.86

P;P

Vest4

0.14

MPC

0.35

ClinPred

0.034

GERP RS

4.0

Varity_R

0.55

gMVP

0.43

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.36

Details are displayed if max score is > 0.2

DS_AG_spliceai

0.36

Position offset: 15

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over