dbSNP rs465899: APC:p.Pro1960Pro (chr5-112841474-G-A) – ACMG Classification: Benign (-21 pts)

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_000038.6(APC):c.5880G>A(p.Pro1960Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.625 in 1,612,952 control chromosomes in the GnomAD database, including 318,251 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.60 ( 28088 hom., cov: 32)

Exomes 𝑓: 0.63 ( 290163 hom. )

Consequence

APC
NM_000038.6 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:18O:1

Conservation

PhyloP100: -0.146

Publications

70 publications found

Variant links:

Genes affected

APC (HGNC:583): (APC regulator of WNT signaling pathway) This gene encodes a tumor suppressor protein that acts as an antagonist of the Wnt signaling pathway. It is also involved in other processes including cell migration and adhesion, transcriptional activation, and apoptosis. Defects in this gene cause familial adenomatous polyposis (FAP), an autosomal dominant pre-malignant disease that usually progresses to malignancy. Mutations in the APC gene have been found to occur in most colorectal cancers, where disease-associated mutations tend to be clustered in a small region designated the mutation cluster region (MCR) and result in a truncated protein product. [provided by RefSeq, Jun 2022]

APC Gene-Disease associations (from GenCC):

classic or attenuated familial adenomatous polyposis
Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
desmoid tumor
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Genomics England PanelApp
familial adenomatous polyposis 1
Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Ambry Genetics
gastric adenocarcinoma and proximal polyposis of the stomach
Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Ambry Genetics, ClinGen, Labcorp Genetics (formerly Invitae)
sarcoma
Inheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp
APC-related attenuated familial adenomatous polyposis
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
Turcot syndrome with polyposis
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
Cenani-Lenz syndactyly syndrome
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

APC links:

ENSG00000258864 (HGNC:):

ENSG00000258864 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.58).

BP6

Variant 5-112841474-G-A is Benign according to our data. Variant chr5-112841474-G-A is described in ClinVar as Benign. ClinVar VariationId is 42247.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-0.146 with no splicing effect.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.8 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000038.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
APC	NM_000038.6	MANE Select	c.5880G>A	p.Pro1960Pro	synonymous	Exon 16 of 16	NP_000029.2
APC	NM_001407446.1		c.5964G>A	p.Pro1988Pro	synonymous	Exon 16 of 16	NP_001394375.1
APC	NM_001354896.2		c.5934G>A	p.Pro1978Pro	synonymous	Exon 17 of 17	NP_001341825.1	R4GMU6

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
APC	ENST00000257430.9	TSL:5 MANE Select	c.5880G>A	p.Pro1960Pro	synonymous	Exon 16 of 16	ENSP00000257430.4	P25054-1
APC	ENST00000508376.6	TSL:1	c.5880G>A	p.Pro1960Pro	synonymous	Exon 17 of 17	ENSP00000427089.2	P25054-1
APC	ENST00000508624.5	TSL:1	n.*5202G>A		non_coding_transcript_exon	Exon 17 of 17	ENSP00000424265.1	E7EMH9

Frequencies

GnomAD3 genomes

AF:

0.603

AC:

91542

AN:

151868

Hom.:

28071

Cov.:

show subpopulations

Gnomad AFR

AF:

0.538

Gnomad AMI

AF:

0.615

Gnomad AMR

AF:

0.669

Gnomad ASJ

AF:

0.567

Gnomad EAS

AF:

0.821

Gnomad SAS

AF:

0.730

Gnomad FIN

AF:

0.537

Gnomad MID

AF:

0.623

Gnomad NFE

AF:

0.613

Gnomad OTH

AF:

0.613

GnomAD2 exomes

AF:

0.650

AC:

162882

AN:

250700

AF XY:

0.649

show subpopulations

Gnomad AFR exome

AF:

0.537

Gnomad AMR exome

AF:

0.734

Gnomad ASJ exome

AF:

0.582

Gnomad EAS exome

AF:

0.822

Gnomad FIN exome

AF:

0.559

Gnomad NFE exome

AF:

0.619

Gnomad OTH exome

AF:

0.651

GnomAD4 exome

AF:

0.628

AC:

916872

AN:

1460966

Hom.:

290163

Cov.:

AF XY:

0.630

AC XY:

457549

AN XY:

726812

show subpopulations

African (AFR)

AF:

0.525

AC:

17565

AN:

33456

American (AMR)

AF:

0.727

AC:

32488

AN:

44710

Ashkenazi Jewish (ASJ)

AF:

0.582

AC:

15204

AN:

26124

East Asian (EAS)

AF:

0.840

AC:

33350

AN:

39684

South Asian (SAS)

AF:

0.709

AC:

61108

AN:

86234

European-Finnish (FIN)

AF:

0.573

AC:

30583

AN:

53400

Middle Eastern (MID)

AF:

0.616

AC:

3550

AN:

5766

European-Non Finnish (NFE)

AF:

0.616

AC:

684812

AN:

1111226

Other (OTH)

AF:

0.633

AC:

38212

AN:

60366

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.480

Heterozygous variant carriers

21607

43213

64820

86426

108033

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

18538

37076

55614

74152

92690

<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:

0.603

AC:

91611

AN:

151986

Hom.:

28088

Cov.:

AF XY:

0.604

AC XY:

44909

AN XY:

74292

show subpopulations

African (AFR)

AF:

0.538

AC:

22303

AN:

41428

American (AMR)

AF:

0.670

AC:

10224

AN:

15268

Ashkenazi Jewish (ASJ)

AF:

0.567

AC:

1968

AN:

3468

East Asian (EAS)

AF:

0.821

AC:

4238

AN:

5164

South Asian (SAS)

AF:

0.730

AC:

3518

AN:

4818

European-Finnish (FIN)

AF:

0.537

AC:

5671

AN:

10556

Middle Eastern (MID)

AF:

0.633

AC:

186

AN:

294

European-Non Finnish (NFE)

AF:

0.613

AC:

41653

AN:

67966

Other (OTH)

AF:

0.610

AC:

1290

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

1842

3685

5527

7370

9212

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

766

1532

2298

3064

3830

<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:

0.615

Hom.:

120541

Bravo

AF:

0.611

Asia WGS

AF:

0.753

AC:

2616

AN:

3478

EpiCase

AF:

0.610

EpiControl

AF:

0.613

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (8)

Hereditary cancer-predisposing syndrome (4)

Familial adenomatous polyposis 1 (2)

not provided (2)

APC-Associated Polyposis Disorders (1)

Carcinoma of colon (1)

Familial colorectal cancer (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.58

CADD

Benign

7.3

(source)

DANN

Benign

0.70

PhyloP100

-0.15

Mutation Taster

=94/6

polymorphism (auto)

(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