dbSNP rs76267164: FCN2:p.Arg311Gln (chr9-134887405-G-A) – ACMG Classification: Benign (-8 pts)

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_004108.3(FCN2):c.932G>A(p.Arg311Gln) variant causes a missense change. The variant allele was found at a frequency of 0.00481 in 1,613,996 control chromosomes in the GnomAD database, including 57 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as association (★).

Frequency

Genomes: 𝑓 0.0034 ( 5 hom., cov: 33)

Exomes 𝑓: 0.0050 ( 52 hom. )

Consequence

FCN2
NM_004108.3 missense

Scores

Clinical Significance

association criteria provided, single submitter O:1

Conservation

PhyloP100: 6.64

Publications

16 publications found

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 was made for transcript

Our verdict: Benign. The variant received -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.012019813).

BS2

High Homozygotes in GnomAd4 at 5 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FCN2	NM_004108.3 link	c.932G>A	p.Arg311Gln	missense_variant	Exon 8 of 8	ENST00000291744.11	NP_004099.2	Q15485-1
FCN2	NM_015837.3 link	c.818G>A	p.Arg273Gln	missense_variant	Exon 7 of 7		NP_056652.1	Q15485-2
FCN2	XM_011518392.4 link	c.899G>A	p.Arg300Gln	missense_variant	Exon 8 of 8		XP_011516694.1
FCN2	XM_006717015.5 link	c.785G>A	p.Arg262Gln	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.932G>A	p.Arg311Gln	missense_variant	Exon 8 of 8	1	NM_004108.3	ENSP00000291744.6		Q15485-1
FCN2	ENST00000350339.3 link	c.818G>A	p.Arg273Gln	missense_variant	Exon 7 of 7	5		ENSP00000291741.5		Q15485-2

Frequencies

GnomAD3 genomes

AF:

0.00339

AC:

516

AN:

152100

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00109

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00812

Gnomad ASJ

AF:

0.00259

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00891

Gnomad FIN

AF:

0.0000943

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.00410

Gnomad OTH

AF:

0.00624

GnomAD2 exomes

AF:

0.00443

AC:

1111

AN:

250532

AF XY:

0.00472

show subpopulations

Gnomad AFR exome

AF:

0.000616

Gnomad AMR exome

AF:

0.00827

Gnomad ASJ exome

AF:

0.00327

Gnomad EAS exome

AF:

0.000163

Gnomad FIN exome

AF:

0.000185

Gnomad NFE exome

AF:

0.00410

Gnomad OTH exome

AF:

0.0104

GnomAD4 exome

AF:

0.00496

AC:

7250

AN:

1461780

Hom.:

Cov.:

AF XY:

0.00504

AC XY:

3663

AN XY:

727198

show subpopulations

African (AFR)

AF:

0.000777

AC:

AN:

33480

American (AMR)

AF:

0.00807

AC:

361

AN:

44716

Ashkenazi Jewish (ASJ)

AF:

0.00264

AC:

AN:

26136

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39700

South Asian (SAS)

AF:

0.00790

AC:

681

AN:

86242

European-Finnish (FIN)

AF:

0.000112

AC:

AN:

53394

Middle Eastern (MID)

AF:

0.00260

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00520

AC:

5786

AN:

1111956

Other (OTH)

AF:

0.00505

AC:

305

AN:

60388

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.474

Heterozygous variant carriers

384

768

1153

1537

1921

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

240

480

720

960

1200

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00340

AC:

517

AN:

152216

Hom.:

Cov.:

AF XY:

0.00320

AC XY:

238

AN XY:

74440

show subpopulations

African (AFR)

AF:

0.00108

AC:

AN:

41534

American (AMR)

AF:

0.00817

AC:

125

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.00259

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5176

South Asian (SAS)

AF:

0.00892

AC:

AN:

4820

European-Finnish (FIN)

AF:

0.0000943

AC:

AN:

10600

Middle Eastern (MID)

AF:

0.00680

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00410

AC:

279

AN:

68010

Other (OTH)

AF:

0.00618

AC:

AN:

2104

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

114

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00375

Hom.:

Bravo

AF:

0.00402

TwinsUK

AF:

0.00512

AC:

ALSPAC

AF:

0.00545

AC:

ESP6500AA

AF:

0.00113

AC:

ESP6500EA

AF:

0.00384

AC:

ExAC

AF:

0.00446

AC:

542

Asia WGS

AF:

0.00346

AC:

AN:

3478

EpiCase

AF:

0.00463

EpiControl

AF:

0.00409

ClinVar

Significance: association

Submissions summary: Other:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Other:1

Aug 30, 2022

Population Bio, Inc.

Significance:association

Review Status:criteria provided, single submitter

Collection Method:case-control

FCN2 variant c.932G>A (rs76267164) is associated with Progressive multifocal leukoencephalopathy (PML, ORPHA:217260). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.24

BayesDel_addAF

Benign

-0.26

BayesDel_noAF

Benign

-0.15

CADD

Benign

(source)

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.085

T;.

Eigen

Uncertain

0.49

Eigen_PC

Uncertain

0.30

FATHMM_MKL

Uncertain

0.92

LIST_S2

Benign

0.82

T;T

MetaRNN

Benign

0.012

T;T

MetaSVM

Uncertain

0.33

MutationAssessor

Pathogenic

3.0

M;.

PhyloP100

6.6

PrimateAI

Benign

0.35

PROVEAN

Uncertain

-3.2

D;D

REVEL

Uncertain

0.59

Sift

Benign

0.031

D;D

Sift4G

Uncertain

0.0020

D;D

Polyphen

1.0

D;D

Vest4

0.54

MVP

0.80

MPC

0.44

ClinPred

0.041

GERP RS

3.1

Varity_R

0.62

gMVP

0.76

Mutation Taster

=71/29

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over