chr9-134887245-G-T

Variant names:

• chr9-134887245-G-T
• rs7851696
• NM_004108.3:c.772G>T

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP6 BA1

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).

• Frequency:
  • Genomes: 𝑓 0.13 (1456 hom., cov: 33)
  • Exomes 𝑓: 0.12 (10294 hom.)
• Consequence: FCN2 NM_004108.3 missense
• Clinical Significance: Benign no assertion criteria provided B:1
• Conservation: PhyloP100: 6.35
• Publications: 82 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 -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 VariationId 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.

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.772G>T	p.Ala258Ser	missense	Exon 8 of 8	NP_004099.2
	FCN2	NM_015837.3		c.658G>T	p.Ala220Ser	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.772G>T	p.Ala258Ser	missense	Exon 8 of 8	ENSP00000291744.6
	FCN2	ENST00000350339.3	TSL:5	c.658G>T	p.Ala220Ser	missense	Exon 7 of 7	ENSP00000291741.5

Frequencies

GnomAD3 genomes AF: 0.135 AC: 20474 AN: 152124 Hom.: 1456 Cov.: 33

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

GnomAD2 exomes AF: 0.125 AC: 31345 AN: 251484 AF XY: 0.123

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 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.: 36 AF XY: 0.115 AC XY: 83401 AN XY: 727180

African (AFR) AF: 0.199 AC: 6665 AN: 33478

American (AMR) AF: 0.145 AC: 6491 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0469 AC: 1225 AN: 26136

East Asian (EAS) AF: 0.158 AC: 6264 AN: 39698

South Asian (SAS) AF: 0.123 AC: 10607 AN: 86258

European-Finnish (FIN) AF: 0.104 AC: 5567 AN: 53420

Middle Eastern (MID) AF: 0.0683 AC: 394 AN: 5766

European-Non Finnish (NFE) AF: 0.112 AC: 124446 AN: 1111888

Other (OTH) AF: 0.112 AC: 6780 AN: 60390

GnomAD4 genome AF: 0.135 AC: 20497 AN: 152242 Hom.: 1456 Cov.: 33 AF XY: 0.133 AC XY: 9896 AN XY: 74438

African (AFR) AF: 0.194 AC: 8045 AN: 41546

American (AMR) AF: 0.126 AC: 1921 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.0418 AC: 145 AN: 3472

East Asian (EAS) AF: 0.178 AC: 921 AN: 5174

South Asian (SAS) AF: 0.122 AC: 588 AN: 4824

European-Finnish (FIN) AF: 0.0950 AC: 1007 AN: 10604

Middle Eastern (MID) AF: 0.0374 AC: 11 AN: 294

European-Non Finnish (NFE) AF: 0.111 AC: 7565 AN: 68016

Other (OTH) AF: 0.130 AC: 275 AN: 2112

Alfa AF: 0.118 Hom.: 4039

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

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 v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.43	T
BayesDel_noAF	Benign	-0.25
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.090	T
Eigen	Uncertain	0.36
Eigen_PC	Benign	0.18
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.81	T
MetaRNN	Benign	0.0026	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.2	M
PhyloP100		6.4
PrimateAI	Benign	0.43	T
PROVEAN	Uncertain	-2.7	D
REVEL	Uncertain	0.47
Sift	Uncertain	0.022	D
Sift4G	Uncertain	0.014	D
Polyphen		0.86	P
Vest4		0.14
MPC		0.35
ClinPred		0.034	T
GERP RS		4.0
Varity_R		0.55
gMVP		0.43
Mutation Taster		=83/17	polymorphism (auto)

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

Other links and lift over

dbSNP: rs7851696; hg19: chr9-137779091; COSMIC: COSV52476296;