rs7851696

chr9-134887245-G-Cchr9-134887245-G-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_004108.3(FCN2):c.772G>C(p.Ala258Pro) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A258S) has been classified as Benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: FCN2 NM_004108.3 missense
• Clinical Significance: Not reported in ClinVar
• 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 Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.976

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FCN2	NM_004108.3	c.772G>C	p.Ala258Pro	missense_variant	8/8	ENST00000291744.11
FCN2	NM_015837.3	c.658G>C	p.Ala220Pro	missense_variant	7/7
FCN2	XM_011518392.4	c.739G>C	p.Ala247Pro	missense_variant	8/8
FCN2	XM_006717015.5	c.625G>C	p.Ala209Pro	missense_variant	7/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FCN2	ENST00000291744.11	c.772G>C	p.Ala258Pro	missense_variant	8/8	1	NM_004108.3	P1
FCN2	ENST00000350339.3	c.658G>C	p.Ala220Pro	missense_variant	7/7	5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 36

GnomAD4 genome Cov.: 33

ExAC AF: 0.00000824 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.78
BayesDel_addAF	Pathogenic	0.31	D
BayesDel_noAF	Pathogenic	0.21
Cadd	Uncertain	23
Dann	Uncertain	1.0
DEOGEN2	Benign	0.087	T;.
Eigen	Uncertain	0.53
Eigen_PC	Uncertain	0.29
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.82	T;T
M_CAP	Uncertain	0.091	D
MetaRNN	Pathogenic	0.98	D;D
MetaSVM	Uncertain	0.77	D
MutationAssessor	Pathogenic	3.2	M;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Benign	0.48	T
PROVEAN	Pathogenic	-4.7	D;D
REVEL	Pathogenic	0.72
Sift	Uncertain	0.0090	D;D
Sift4G	Uncertain	0.0060	D;D
Polyphen		1.0	D;D
Vest4		0.83
MutPred		0.77		Loss of catalytic residue at A258 (P = 0.1025);.;
MVP		0.86
MPC		0.47
ClinPred		0.98	D
GERP RS		4.0
Varity_R		0.86
gMVP		0.83

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.090		Details are displayed if max score is > 0.2

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;