9-134887405-G-A

Variant names:

• chr9-134887405-G-A
• rs76267164
• NM_004108.3:c.932G>A

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Strong BS2

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
• Clinical Significance: association criteria provided, single submitter O:1
• Conservation: PhyloP100: 6.64
• Publications: 16 publications found

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

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

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004108.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FCN2	NM_004108.3	MANE Select	c.932G>A	p.Arg311Gln	missense	Exon 8 of 8	NP_004099.2
	FCN2	NM_015837.3		c.818G>A	p.Arg273Gln	missense	Exon 7 of 7	NP_056652.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FCN2	ENST00000291744.11	TSL:1 MANE Select	c.932G>A	p.Arg311Gln	missense	Exon 8 of 8	ENSP00000291744.6
	FCN2	ENST00000350339.3	TSL:5	c.818G>A	p.Arg273Gln	missense	Exon 7 of 7	ENSP00000291741.5

Frequencies

GnomAD3 genomes AF: 0.00339 AC: 516 AN: 152100 Hom.: 5 Cov.: 33

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

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.: 52 Cov.: 35 AF XY: 0.00504 AC XY: 3663 AN XY: 727198

African (AFR) AF: 0.000777 AC: 26 AN: 33480

American (AMR) AF: 0.00807 AC: 361 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.00264 AC: 69 AN: 26136

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.00790 AC: 681 AN: 86242

European-Finnish (FIN) AF: 0.000112 AC: 6 AN: 53394

Middle Eastern (MID) AF: 0.00260 AC: 15 AN: 5768

European-Non Finnish (NFE) AF: 0.00520 AC: 5786 AN: 1111956

Other (OTH) AF: 0.00505 AC: 305 AN: 60388

GnomAD4 genome AF: 0.00340 AC: 517 AN: 152216 Hom.: 5 Cov.: 33 AF XY: 0.00320 AC XY: 238 AN XY: 74440

African (AFR) AF: 0.00108 AC: 45 AN: 41534

American (AMR) AF: 0.00817 AC: 125 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00259 AC: 9 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.00892 AC: 43 AN: 4820

European-Finnish (FIN) AF: 0.0000943 AC: 1 AN: 10600

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.00410 AC: 279 AN: 68010

Other (OTH) AF: 0.00618 AC: 13 AN: 2104

Alfa AF: 0.00375 Hom.: 6

Bravo AF: 0.00402

TwinsUK AF: 0.00512 AC: 19

ALSPAC AF: 0.00545 AC: 21

ESP6500AA AF: 0.00113 AC: 5

ESP6500EA AF: 0.00384 AC: 33

ExAC AF: 0.00446 AC: 542

Asia WGS AF: 0.00346 AC: 12 AN: 3478

EpiCase AF: 0.00463

EpiControl AF: 0.00409

ClinVar

Significance: association

Submissions summary: Other:1

Revision: criteria provided, single submitter

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 v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.24
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.15
CADD	Benign	23
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.085	T
Eigen	Uncertain	0.49
Eigen_PC	Uncertain	0.30
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.82	T
MetaRNN	Benign	0.012	T
MetaSVM	Uncertain	0.33	D
MutationAssessor	Pathogenic	3.0	M
PhyloP100		6.6
PrimateAI	Benign	0.35	T
PROVEAN	Uncertain	-3.2	D
REVEL	Uncertain	0.59
Sift	Benign	0.031	D
Sift4G	Uncertain	0.0020	D
Polyphen		1.0	D
Vest4		0.54
MVP		0.80
MPC		0.44
ClinPred		0.041	T
GERP RS		3.1
Varity_R		0.62
gMVP		0.76
Mutation Taster		=71/29	polymorphism

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

Other links and lift over

dbSNP: rs76267164; hg19: chr9-137779251;