19-1453161-G-A

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_005883.3(APC2):c.141+19G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.013 in 1,591,302 control chromosomes in the GnomAD database, including 2,197 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.068 ( 1150 hom., cov: 33)

Exomes 𝑓: 0.0072 ( 1047 hom. )

Consequence

APC2
NM_005883.3 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -0.192

Publications

1 publications found

Variant links:

Genes affected

APC2 (HGNC:24036): (APC regulator of WNT signaling pathway 2) This gene encodes a strongly conserved protein that has an N-terminal coiled-coil domain followed by an armadillo domain, five 20-amino acid repeats, and two SAMP domains. This protein promotes the assembly of a multiprotein complex that recruits and phosphorylates the Wnt effector beta-catenin and targets beta-catenin for ubiquitylation and proteasomal degradation. This protein therefore plays a role in the reduction of cytoplasmic levels of beta-catenin which in turn reduces activation of Wnt target genes that play a pivotal role in the pathogenesis of various human cancers. The protein encoded by this gene is closely related to the adenomatous polyposis coli (APC) tumor-suppressor protein and has similar tumor-suppressor effects. This gene also plays a role in actin assembly, cell-cell adhesion, and microtubule network formation through its interaction with cytoskeletal proteins. This gene has its highest expression in the central nervous system and is involved in brain development through cytoskeletal regulation in neurons. Alternative splicing produces multiple transcript variants encoding distinct isoforms. [provided by RefSeq, May 2017]

APC2 Gene-Disease associations (from GenCC):

cortical dysplasia, complex, with other brain malformations 10
Inheritance: AR Classification: STRONG, MODERATE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P
lissencephaly spectrum disorders
Inheritance: AR Classification: STRONG Submitted by: ClinGen
Sotos syndrome
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
intellectual developmental disorder, autosomal recessive 74
Inheritance: Unknown Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

APC2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.81).

BP6

Variant 19-1453161-G-A is Benign according to our data. Variant chr19-1453161-G-A is described in ClinVar as Benign. ClinVar VariationId is 1599767.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.231 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005883.3. 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
	APC2	NM_005883.3	MANE Select	c.141+19G>A		intron	N/A	NP_005874.1	O95996-1
	APC2	NM_001351273.1		c.141+19G>A		intron	N/A	NP_001338202.1	O95996-3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
APC2	ENST00000590469.6	TSL:1 MANE Select	c.141+19G>A	intron	N/A	ENSP00000467073.2	O95996-1
APC2	ENST00000233607.6	TSL:1	c.141+19G>A	intron	N/A	ENSP00000233607.2	O95996-1
APC2	ENST00000535453.5	TSL:1	c.141+19G>A	intron	N/A	ENSP00000442954.1	O95996-1

Frequencies

GnomAD3 genomes

AF:

0.0678

AC:

10308

AN:

152134

Hom.:

1141

Cov.:

show subpopulations

Gnomad AFR

AF:

0.235

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0273

Gnomad ASJ

AF:

0.00202

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000414

Gnomad FIN

AF:

0.000188

Gnomad MID

AF:

0.0127

Gnomad NFE

AF:

0.000838

Gnomad OTH

AF:

0.0440

GnomAD2 exomes

AF:

0.0169

AC:

3534

AN:

208608

AF XY:

0.0122

show subpopulations

Gnomad AFR exome

AF:

0.239

Gnomad AMR exome

AF:

0.0131

Gnomad ASJ exome

AF:

0.00152

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000280

Gnomad NFE exome

AF:

0.00110

Gnomad OTH exome

AF:

0.00926

GnomAD4 exome

AF:

0.00716

AC:

10302

AN:

1439050

Hom.:

1047

Cov.:

AF XY:

0.00621

AC XY:

4434

AN XY:

713838

show subpopulations

African (AFR)

AF:

0.243

AC:

8019

AN:

32984

American (AMR)

AF:

0.0149

AC:

610

AN:

40954

Ashkenazi Jewish (ASJ)

AF:

0.00132

AC:

AN:

25690

East Asian (EAS)

AF:

0.0000259

AC:

AN:

38572

South Asian (SAS)

AF:

0.000503

AC:

AN:

83480

European-Finnish (FIN)

AF:

0.000528

AC:

AN:

51158

Middle Eastern (MID)

AF:

0.0160

AC:

AN:

5250

European-Non Finnish (NFE)

AF:

0.000520

AC:

573

AN:

1101442

Other (OTH)

AF:

0.0153

AC:

912

AN:

59520

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.487

Heterozygous variant carriers

509

1018

1527

2036

2545

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

246

492

738

984

1230

<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:

0.0680

AC:

10353

AN:

152252

Hom.:

1150

Cov.:

AF XY:

0.0672

AC XY:

5002

AN XY:

74446

show subpopulations

African (AFR)

AF:

0.235

AC:

9772

AN:

41516

American (AMR)

AF:

0.0272

AC:

417

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.00202

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5182

South Asian (SAS)

AF:

0.000207

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.000188

AC:

AN:

10620

Middle Eastern (MID)

AF:

0.0136

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000838

AC:

AN:

68010

Other (OTH)

AF:

0.0440

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

406

812

1219

1625

2031

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

188

282

376

470

<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:

0.0362

Hom.:

Bravo

AF:

0.0770

Asia WGS

AF:

0.0200

AC:

AN:

3478

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.81

CADD

Benign

3.7

(source)

DANN

Benign

0.84

PhyloP100

-0.19

PromoterAI

0.027

Neutral

(source)

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.17

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