rs1060502518

Variant names:

• chr9-95249136-C-G
• rs1060502518
• NM_000136.3:c.156G>C

Your query was ambiguous. Multiple possible variants found:

• chr9-95249136-C-G
• chr9-95249136-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_000136.3(FANCC):​c.156G>C​(p.Leu52Phe) 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 pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: FANCC NM_000136.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 0.967

Genes affected

FANCC (HGNC:3584): (FA complementation group C) The Fanconi anemia complementation group (FANC) currently includes FANCA, FANCB, FANCC, FANCD1 (also called BRCA2), FANCD2, FANCE, FANCF, FANCG, FANCI, FANCJ (also called BRIP1), FANCL, FANCM and FANCN (also called PALB2). The previously defined group FANCH is the same as FANCA. Fanconi anemia is a genetically heterogeneous recessive disorder characterized by cytogenetic instability, hypersensitivity to DNA crosslinking agents, increased chromosomal breakage, and defective DNA repair. The members of the Fanconi anemia complementation group do not share sequence similarity; they are related by their assembly into a common nuclear protein complex. This gene encodes the protein for complementation group C. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.852

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FANCC	NM_000136.3	c.156G>C	p.Leu52Phe	missense_variant	Exon 2 of 15	ENST00000289081.8	NP_000127.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FANCC	ENST00000289081.8	c.156G>C	p.Leu52Phe	missense_variant	Exon 2 of 15	1	NM_000136.3	ENSP00000289081.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

EpiCase AF: 0.000109

EpiControl AF: 0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Fanconi anemia Uncertain:2

Apr 13, 2021

Natera, Inc.

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Sep 01, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces leucine with phenylalanine at codon 52 of the FANCC protein (p.Leu52Phe). The leucine residue is highly conserved and there is a small physicochemical difference between leucine and phenylalanine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals affected with FANCC-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Hereditary cancer-predisposing syndrome Uncertain:1

Mar 15, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.L52F variant (also known as c.156G>C), located in coding exon 1 of the FANCC gene, results from a G to C substitution at nucleotide position 156. The leucine at codon 52 is replaced by phenylalanine, an amino acid with highly similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.25
BayesDel_addAF	Uncertain	0.060	T
BayesDel_noAF	Benign	-0.15
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.43	T;T;T;.;T;.;.;.
Eigen	Uncertain	0.28
Eigen_PC	Uncertain	0.23
FATHMM_MKL	Uncertain	0.77	D
LIST_S2	Benign	0.83	.;T;T;T;T;T;T;T
M_CAP	Benign	0.031	D
MetaRNN	Pathogenic	0.85	D;D;D;D;D;D;D;D
MetaSVM	Benign	-0.43	T
MutationAssessor	Uncertain	2.4	M;M;.;.;.;.;.;.
PrimateAI	Benign	0.43	T
PROVEAN	Uncertain	-3.3	D;D;.;.;D;.;.;.
REVEL	Uncertain	0.41
Sift	Uncertain	0.0050	D;D;.;.;D;.;.;.
Sift4G	Uncertain	0.011	D;D;D;.;D;.;.;.
Polyphen		1.0	D;D;.;.;D;.;.;.
Vest4		0.42
MutPred		0.82		Gain of methylation at K53 (P = 0.0293);Gain of methylation at K53 (P = 0.0293);Gain of methylation at K53 (P = 0.0293);Gain of methylation at K53 (P = 0.0293);Gain of methylation at K53 (P = 0.0293);Gain of methylation at K53 (P = 0.0293);Gain of methylation at K53 (P = 0.0293);Gain of methylation at K53 (P = 0.0293);
MVP		0.86
MPC		0.36
ClinPred		0.97	D
GERP RS		3.3
Varity_R		0.27
gMVP		0.51

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: rs1060502518; hg19: chr9-98011418;