9-134887245-G-T

Variant names:

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

Variant summary

Our verdict is Benign. Variant got -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). 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
• Clinical Significance: Benign no assertion criteria provided B:1
• Conservation: PhyloP100: 6.35

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 -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	c.772G>T	p.Ala258Ser	missense_variant	Exon 8 of 8	ENST00000291744.11	NP_004099.2
FCN2	NM_015837.3	c.658G>T	p.Ala220Ser	missense_variant	Exon 7 of 7		NP_056652.1
FCN2	XM_011518392.4	c.739G>T	p.Ala247Ser	missense_variant	Exon 8 of 8		XP_011516694.1
FCN2	XM_006717015.5	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	c.772G>T	p.Ala258Ser	missense_variant	Exon 8 of 8	1	NM_004108.3	ENSP00000291744.6
FCN2	ENST00000350339.3	c.658G>T	p.Ala220Ser	missense_variant	Exon 7 of 7	5		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

GnomAD3 exomes AF: 0.125 AC: 31345 AN: 251484 Hom.: 2226 AF XY: 0.123 AC XY: 16655 AN XY: 135916

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

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.: 33 AF XY: 0.133 AC XY: 9896 AN XY: 74438

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

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	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;T
MetaRNN	Benign	0.0026	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.2	M;.
PrimateAI	Benign	0.43	T
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	T
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

Other links and lift over

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