7-77199184-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_006682.3(FGL2):c.610C>G(p.Pro204Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: FGL2 NM_006682.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.48

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.27233085).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FGL2	NM_006682.3	c.610C>G	p.Pro204Ala	missense_variant	1/2	ENST00000248598.6
CCDC146	NM_020879.3	c.156+31360G>C		intron_variant		ENST00000285871.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FGL2	ENST00000248598.6	c.610C>G	p.Pro204Ala	missense_variant	1/2	1	NM_006682.3	P1
CCDC146	ENST00000285871.5	c.156+31360G>C		intron_variant		1	NM_020879.3	P1
CCDC146	ENST00000415750.5	c.156+31360G>C		intron_variant		4
FGL2	ENST00000637771.2	n.665C>G		non_coding_transcript_exon_variant	1/1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 04, 2022

The c.610C>G (p.P204A) alteration is located in exon 1 (coding exon 1) of the FGL2 gene. This alteration results from a C to G substitution at nucleotide position 610, causing the proline (P) at amino acid position 204 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	0.082
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.40
Cadd	Benign	22
Dann	Uncertain	0.99
DEOGEN2	Uncertain	0.44	T;T
Eigen	Uncertain	0.28
Eigen_PC	Uncertain	0.31
FATHMM_MKL	Benign	0.74	D
LIST_S2	Benign	0.76	T;T
M_CAP	Benign	0.0033	T
MetaRNN	Benign	0.25	T;T
MetaSVM	Benign	-0.82	T
MutationAssessor	Benign	1.9	M;.
MutationTaster	Benign	0.95	D;D;N
PrimateAI	Benign	0.36	T
PROVEAN	Uncertain	-2.5	N;.
REVEL	Benign	0.11
Sift	Benign	0.082	T;.
Sift4G	Benign	0.073	T;.
Polyphen		0.85	P;.
Vest4		0.17
MutPred		0.35		Loss of disorder (P = 0.0753);Loss of disorder (P = 0.0753);
MVP		0.73
MPC		0.15
ClinPred		0.73	D
GERP RS		5.3
Varity_R		0.072
gMVP		0.45

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: rs1791931561; hg19: chr7-76828501;