9-95149977-G-C

Variant names:

• chr9-95149977-G-C
• rs140781259
• NM_000136.3:c.632C>G

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_Strong BP6

The NM_000136.3(FANCC):​c.632C>G​(p.Pro211Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00124 in 1,613,068 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P211L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0014 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0012 (1 hom.)
• Consequence: FANCC NM_000136.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4 B:11 O:1
• Conservation: PhyloP100: 5.71
• Publications: 10 publications found

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]

AOPEP (HGNC:1361): (aminopeptidase O (putative)) This gene encodes a member of the M1 zinc aminopeptidase family. The encoded protein is a zinc-dependent metallopeptidase that catalyzes the removal of an amino acid from the amino terminus of a protein or peptide. This protein may play a role in the generation of angiotensin IV. Alternate splicing results in multiple transcript variants. [provided by RefSeq, Oct 2010]

ACMG classification

Our verdict: Likely_benign. The variant received -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.010762483).
• BP6: Variant 9-95149977-G-C is Benign according to our data. Variant chr9-95149977-G-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 127544.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000136.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FANCC	NM_000136.3	MANE Select	c.632C>G	p.Pro211Arg	missense	Exon 7 of 15	NP_000127.2	Q00597
	FANCC	NM_001243743.2		c.632C>G	p.Pro211Arg	missense	Exon 7 of 15	NP_001230672.1	A0A024R9N2
	FANCC	NM_001243744.2		c.632C>G	p.Pro211Arg	missense	Exon 7 of 14	NP_001230673.1	A0A087WW44

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FANCC	ENST00000289081.8	TSL:1 MANE Select	c.632C>G	p.Pro211Arg	missense	Exon 7 of 15	ENSP00000289081.3	Q00597
	FANCC	ENST00000375305.6	TSL:1	c.632C>G	p.Pro211Arg	missense	Exon 7 of 15	ENSP00000364454.1	Q00597
	FANCC	ENST00000490972.7	TSL:1	c.632C>G	p.Pro211Arg	missense	Exon 7 of 14	ENSP00000479931.1	A0A087WW44

Frequencies

GnomAD3 genomes AF: 0.00143 AC: 218 AN: 152154 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000265

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000328

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00867

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00157

Gnomad OTH AF: 0.000955

GnomAD2 exomes AF: 0.00126 AC: 313 AN: 249292 AF XY: 0.00128

Gnomad AFR exome AF: 0.000312

Gnomad AMR exome AF: 0.000204

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00792

Gnomad NFE exome AF: 0.00108

Gnomad OTH exome AF: 0.00115

GnomAD4 exome AF: 0.00122 AC: 1782 AN: 1460796 Hom.: 1 Cov.: 32 AF XY: 0.00115 AC XY: 837 AN XY: 726514

African (AFR) AF: 0.0000299 AC: 1 AN: 33474

American (AMR) AF: 0.000135 AC: 6 AN: 44534

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26098

East Asian (EAS) AF: 0.00 AC: 0 AN: 39688

South Asian (SAS) AF: 0.0000349 AC: 3 AN: 85862

European-Finnish (FIN) AF: 0.00749 AC: 400 AN: 53390

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5766

European-Non Finnish (NFE) AF: 0.00118 AC: 1315 AN: 1111618

Other (OTH) AF: 0.000928 AC: 56 AN: 60366

GnomAD4 genome AF: 0.00143 AC: 218 AN: 152272 Hom.: 1 Cov.: 32 AF XY: 0.00173 AC XY: 129 AN XY: 74432

African (AFR) AF: 0.000265 AC: 11 AN: 41558

American (AMR) AF: 0.000327 AC: 5 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5172

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4820

European-Finnish (FIN) AF: 0.00867 AC: 92 AN: 10612

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00157 AC: 107 AN: 68032

Other (OTH) AF: 0.000945 AC: 2 AN: 2116

Alfa AF: 0.00102 Hom.: 0

Bravo AF: 0.000612

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.00104 AC: 4

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000930 AC: 8

ExAC AF: 0.000939 AC: 114

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	3	not specified (5)
-	2	1	not provided (3)
-	-	2	Fanconi anemia (2)
-	1	1	Fanconi anemia complementation group C (2)
-	-	1	FANCC-related disorder (1)
-	-	1	Fanconi anemia complementation group A (1)
-	-	1	Hereditary cancer-predisposing syndrome (1)
-	-	1	Malignant tumor of breast (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.36	T
BayesDel_noAF	Benign	-0.30
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.32	T
Eigen	Uncertain	0.28
Eigen_PC	Uncertain	0.25
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.61	T
M_CAP	Benign	0.021	T
MetaRNN	Benign	0.011	T
MetaSVM	Benign	-0.79	T
MutationAssessor	Uncertain	2.1	M
PhyloP100		5.7
PrimateAI	Benign	0.37	T
PROVEAN	Uncertain	-3.9	D
REVEL	Uncertain	0.29
Sift	Uncertain	0.013	D
Sift4G	Uncertain	0.0050	D
Polyphen		0.92	P
Vest4		0.52
MVP		0.82
MPC		0.34
ClinPred		0.059	T
GERP RS		3.9
Varity_R		0.17
gMVP		0.31
Mutation Taster		=90/10	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs140781259; hg19: chr9-97912259; COSMIC: COSV56662984; COSMIC: COSV56662984;