7-77196856-C-G

Variant names:

• chr7-77196856-C-G
• rs773321059
• NM_006682.3:c.743G>C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_006682.3(FGL2):​c.743G>C​(p.Gly248Ala) variant causes a missense change. The variant allele was found at a frequency of 0.0000322 in 1,461,842 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000032 (0 hom.)
• Consequence: FGL2 NM_006682.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.89

Genes affected

FGL2 (HGNC:3696): (fibrinogen like 2) The protein encoded by this gene is a secreted protein that is similar to the beta- and gamma-chains of fibrinogen. The carboxyl-terminus of the encoded protein consists of the fibrinogen-related domains (FRED). The encoded protein forms a tetrameric complex which is stabilized by interchain disulfide bonds. This protein may play a role in physiologic functions at mucosal sites. [provided by RefSeq, Jul 2008]

CCDC146 (HGNC:29296): (coiled-coil domain containing 146) Located in centriole. [provided by Alliance of Genome Resources, Apr 2022]

ENSG00000259628 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FGL2	NM_006682.3	c.743G>C	p.Gly248Ala	missense_variant	Exon 2 of 2	ENST00000248598.6	NP_006673.1
CCDC146	NM_020879.3	c.156+29032C>G		intron_variant	Intron 2 of 18	ENST00000285871.5	NP_065930.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FGL2	ENST00000248598.6	c.743G>C	p.Gly248Ala	missense_variant	Exon 2 of 2	1	NM_006682.3	ENSP00000248598.5
CCDC146	ENST00000285871.5	c.156+29032C>G		intron_variant	Intron 2 of 18	1	NM_020879.3	ENSP00000285871.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000358 AC: 9 AN: 251160 Hom.: 0 AF XY: 0.0000442 AC XY: 6 AN XY: 135750

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.0000994

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000163

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000264

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000322 AC: 47 AN: 1461842 Hom.: 0 Cov.: 32 AF XY: 0.0000413 AC XY: 30 AN XY: 727226

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000174

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000261

Gnomad4 OTH exome AF: 0.0000331

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000756

ExAC AF: 0.0000247 AC: 3

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Mar 20, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.743G>C (p.G248A) alteration is located in exon 2 (coding exon 2) of the FGL2 gene. This alteration results from a G to C substitution at nucleotide position 743, causing the glycine (G) at amino acid position 248 to be replaced by an alanine (A). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_addAF	Benign	-0.094	T
BayesDel_noAF	Benign	-0.14
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.46	T
Eigen	Uncertain	0.41
Eigen_PC	Uncertain	0.42
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Uncertain	0.90	D
M_CAP	Uncertain	0.11	D
MetaRNN	Uncertain	0.54	D
MetaSVM	Uncertain	0.63	D
MutationAssessor	Pathogenic	3.4	M
PrimateAI	Uncertain	0.50	T
PROVEAN	Pathogenic	-5.0	D
REVEL	Pathogenic	0.65
Sift	Uncertain	0.022	D
Sift4G	Benign	0.083	T
Polyphen		0.26	B
Vest4		0.19
MutPred		0.78		Loss of catalytic residue at M247 (P = 0.1278);
MVP		0.88
MPC		0.38
ClinPred		0.49	T
GERP RS		3.7
Varity_R		0.62
gMVP		0.84

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

Publications

LitVar

Other links and lift over

dbSNP: rs773321059; hg19: chr7-76826173;