Genetic Variant NM_000136.3:c.77C>T (chr9-95249215-G-A) – ACMG Classification: Benign (-13 pts)

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_000136.3(FANCC):c.77C>T(p.Ser26Phe) variant causes a missense change. The variant allele was found at a frequency of 0.00579 in 1,614,112 control chromosomes in the GnomAD database, including 35 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. S26T) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0050 ( 6 hom., cov: 32)

Exomes 𝑓: 0.0059 ( 29 hom. )

Consequence

FANCC
NM_000136.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:21O:1

Conservation

PhyloP100: 3.98

Publications

35 publications found

Variant links:

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]

FANCC Gene-Disease associations (from GenCC):

Fanconi anemia complementation group C
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Myriad Women’s Health, Labcorp Genetics (formerly Invitae), ClinGen, G2P
Fanconi anemia
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
colorectal cancer
Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
malignant pancreatic neoplasm
Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
ovarian cancer
Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
prostate cancer
Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
breast cancer
Inheritance: AD Classification: NO_KNOWN Submitted by: Ambry Genetics

FANCC links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.010334253).

BP6

Variant 9-95249215-G-A is Benign according to our data. Variant chr9-95249215-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 134301.

BS1

Variant frequency is greater than expected in population mid. GnomAdExome4 allele frequency = 0.00587 (8584/1461840) while in subpopulation MID AF = 0.0231 (133/5768). AF 95% confidence interval is 0.0199. There are 29 homozygotes in GnomAdExome4. There are 4198 alleles in the male GnomAdExome4 subpopulation. Median coverage is 31. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 6 AD,AR gene

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
FANCC	NM_000136.3	MANE Select	c.77C>T	p.Ser26Phe	missense	Exon 2 of 15	NP_000127.2	Q00597
FANCC	NM_001243743.2		c.77C>T	p.Ser26Phe	missense	Exon 2 of 15	NP_001230672.1	A0A024R9N2
FANCC	NM_001243744.2		c.77C>T	p.Ser26Phe	missense	Exon 2 of 14	NP_001230673.1	A0A087WW44

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
FANCC	ENST00000289081.8	TSL:1 MANE Select	c.77C>T	p.Ser26Phe	missense	Exon 2 of 15	ENSP00000289081.3	Q00597
FANCC	ENST00000375305.6	TSL:1	c.77C>T	p.Ser26Phe	missense	Exon 2 of 15	ENSP00000364454.1	Q00597
FANCC	ENST00000490972.7	TSL:1	c.77C>T	p.Ser26Phe	missense	Exon 2 of 14	ENSP00000479931.1	A0A087WW44

Frequencies

GnomAD3 genomes

AF:

0.00502

AC:

764

AN:

152154

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000966

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00759

Gnomad ASJ

AF:

0.00720

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00145

Gnomad FIN

AF:

0.00603

Gnomad MID

AF:

0.0190

Gnomad NFE

AF:

0.00713

Gnomad OTH

AF:

0.0101

GnomAD2 exomes

AF:

0.00486

AC:

1220

AN:

251236

AF XY:

0.00465

show subpopulations

Gnomad AFR exome

AF:

0.000738

Gnomad AMR exome

AF:

0.00408

Gnomad ASJ exome

AF:

0.00894

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00564

Gnomad NFE exome

AF:

0.00668

Gnomad OTH exome

AF:

0.00587

GnomAD4 exome

AF:

0.00587

AC:

8584

AN:

1461840

Hom.:

Cov.:

AF XY:

0.00577

AC XY:

4198

AN XY:

727228

show subpopulations

African (AFR)

AF:

0.00167

AC:

AN:

33480

American (AMR)

AF:

0.00367

AC:

164

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00899

AC:

235

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39698

South Asian (SAS)

AF:

0.00185

AC:

160

AN:

86256

European-Finnish (FIN)

AF:

0.00509

AC:

272

AN:

53400

Middle Eastern (MID)

AF:

0.0231

AC:

133

AN:

5768

European-Non Finnish (NFE)

AF:

0.00648

AC:

7205

AN:

1111982

Other (OTH)

AF:

0.00594

AC:

359

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.484

Heterozygous variant carriers

479

958

1437

1916

2395

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

252

504

756

1008

1260

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00502

AC:

764

AN:

152272

Hom.:

Cov.:

AF XY:

0.00506

AC XY:

377

AN XY:

74454

show subpopulations

African (AFR)

AF:

0.000963

AC:

AN:

41546

American (AMR)

AF:

0.00758

AC:

116

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.00720

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5192

South Asian (SAS)

AF:

0.00145

AC:

AN:

4818

European-Finnish (FIN)

AF:

0.00603

AC:

AN:

10606

Middle Eastern (MID)

AF:

0.0204

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00713

AC:

485

AN:

68028

Other (OTH)

AF:

0.00995

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

126

168

210

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00648

Hom.:

Bravo

AF:

0.00443

TwinsUK

AF:

0.00324

AC:

ALSPAC

AF:

0.00752

AC:

ESP6500AA

AF:

0.00136

AC:

ESP6500EA

AF:

0.00686

AC:

ExAC

AF:

0.00465

AC:

565

Asia WGS

AF:

0.00202

AC:

AN:

3478

EpiCase

AF:

0.00698

EpiControl

AF:

0.00842

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (8)

not provided (5)

Fanconi anemia complementation group C (4)

Fanconi anemia (3)

FANCC-related disorder (1)

Fanconi anemia complementation group A (1)

Hereditary cancer-predisposing syndrome (1)

Malignant tumor of breast (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.23

BayesDel_addAF

Benign

-0.33

BayesDel_noAF

Benign

-0.24

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.26

Eigen

Uncertain

0.56

Eigen_PC

Uncertain

0.53

FATHMM_MKL

Uncertain

0.88

LIST_S2

Uncertain

0.88

M_CAP

Benign

0.028

MetaRNN

Benign

0.010

MetaSVM

Benign

-0.49

MutationAssessor

Benign

1.9

PhyloP100

4.0

PrimateAI

Benign

0.38

PROVEAN

Uncertain

-3.5

REVEL

Benign

0.23

Sift

Uncertain

0.0040

Sift4G

Uncertain

0.010

Polyphen

1.0

Vest4

0.26

MVP

0.87

MPC

0.36

ClinPred

0.011

GERP RS

4.2

PromoterAI

0.031

Neutral

(source)

Varity_R

0.20

gMVP

0.23

Mutation Taster

=93/7

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over