9-134885274-C-T

Position:

• chr9-134885274-C-T

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_004108.3(FCN2):​c.337C>T​(p.His113Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00499 in 1,614,156 control chromosomes in the GnomAD database, including 27 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.0037 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0051 (26 hom.)
• Consequence: FCN2 NM_004108.3 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.24

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 -10 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.004905343).
• BP6: Variant 9-134885274-C-T is Benign according to our data. Variant chr9-134885274-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 2659704.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Homozygotes in GnomAdExome4 at 26 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FCN2	NM_004108.3	c.337C>T	p.His113Tyr	missense_variant	5/8	ENST00000291744.11	NP_004099.2
FCN2	NM_015837.3	c.223C>T	p.His75Tyr	missense_variant	4/7		NP_056652.1
FCN2	XM_011518392.4	c.304C>T	p.His102Tyr	missense_variant	5/8		XP_011516694.1
FCN2	XM_006717015.5	c.190C>T	p.His64Tyr	missense_variant	4/7		XP_006717078.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FCN2	ENST00000291744.11	c.337C>T	p.His113Tyr	missense_variant	5/8	1	NM_004108.3	ENSP00000291744.6
FCN2	ENST00000350339.3	c.223C>T	p.His75Tyr	missense_variant	4/7	5		ENSP00000291741.5

Frequencies

GnomAD3 genomes AF: 0.00369 AC: 562 AN: 152202 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000868

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00151

Gnomad ASJ AF: 0.00922

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.0112

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00504

Gnomad OTH AF: 0.00287

GnomAD3 exomes AF: 0.00413 AC: 1038 AN: 251292 Hom.: 1 AF XY: 0.00417 AC XY: 566 AN XY: 135842

Gnomad AFR exome AF: 0.00117

Gnomad AMR exome AF: 0.000607

Gnomad ASJ exome AF: 0.00874

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000849

Gnomad FIN exome AF: 0.0137

Gnomad NFE exome AF: 0.00499

Gnomad OTH exome AF: 0.00342

GnomAD4 exome AF: 0.00512 AC: 7491 AN: 1461836 Hom.: 26 Cov.: 32 AF XY: 0.00507 AC XY: 3686 AN XY: 727236

Gnomad4 AFR exome AF: 0.000896

Gnomad4 AMR exome AF: 0.00110

Gnomad4 ASJ exome AF: 0.00915

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000765

Gnomad4 FIN exome AF: 0.0136

Gnomad4 NFE exome AF: 0.00546

Gnomad4 OTH exome AF: 0.00508

GnomAD4 genome AF: 0.00368 AC: 561 AN: 152320 Hom.: 1 Cov.: 32 AF XY: 0.00368 AC XY: 274 AN XY: 74478

Gnomad4 AFR AF: 0.000866

Gnomad4 AMR AF: 0.00150

Gnomad4 ASJ AF: 0.00922

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000622

Gnomad4 FIN AF: 0.0112

Gnomad4 NFE AF: 0.00503

Gnomad4 OTH AF: 0.00284

Alfa AF: 0.00490 Hom.: 2

Bravo AF: 0.00301

TwinsUK AF: 0.00539 AC: 20

ALSPAC AF: 0.00389 AC: 15

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00547 AC: 47

ExAC AF: 0.00371 AC: 450

EpiCase AF: 0.00425

EpiControl AF: 0.00397

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Jul 01, 2023

FCN2: BP4 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.072
BayesDel_addAF	Benign	-0.57	T
BayesDel_noAF	Benign	-0.58
CADD	Benign	1.8
DANN	Benign	0.70
DEOGEN2	Benign	0.017	T;.
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.033	N
LIST_S2	Benign	0.12	T;T
MetaRNN	Benign	0.0049	T;T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	0.90	L;.
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.40	T
PROVEAN	Benign	-1.4	N;N
REVEL	Benign	0.097
Sift	Benign	0.96	T;T
Sift4G	Benign	0.82	T;T
Polyphen		0.0	B;B
Vest4		0.16
MVP		0.46
MPC		0.083
ClinPred		0.0043	T
GERP RS		-5.5
Varity_R		0.16
gMVP		0.60

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs17549179; hg19: chr9-137777120; COSMIC: COSV99391197;