19-1453094-C-G

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_005883.3(APC2):c.93C>G(p.Asp31Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000124 in 1,608,270 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D31A) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000033 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000010 ( 0 hom. )

Consequence

APC2
NM_005883.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:3

Conservation

PhyloP100: 0.390

Publications

0 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: Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P, PanelApp Australia
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: Likely_benign. The variant received -2 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.17018625).

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.93C>G	p.Asp31Glu	missense	Exon 2 of 15	NP_005874.1	O95996-1
	APC2	NM_001351273.1		c.93C>G	p.Asp31Glu	missense	Exon 1 of 14	NP_001338202.1	O95996-3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
APC2	ENST00000590469.6	TSL:1 MANE Select	c.93C>G	p.Asp31Glu	missense	Exon 2 of 15	ENSP00000467073.2	O95996-1
APC2	ENST00000233607.6	TSL:1	c.93C>G	p.Asp31Glu	missense	Exon 2 of 15	ENSP00000233607.2	O95996-1
APC2	ENST00000535453.5	TSL:1	c.93C>G	p.Asp31Glu	missense	Exon 1 of 14	ENSP00000442954.1	O95996-1

Frequencies

GnomAD3 genomes

AF:

0.0000329

AC:

AN:

152144

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000966

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000503

AC:

AN:

238536

AF XY:

0.0000463

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000358

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000103

AC:

AN:

1456126

Hom.:

Cov.:

AF XY:

0.00000967

AC XY:

AN XY:

723974

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33394

American (AMR)

AF:

0.000340

AC:

AN:

44090

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26030

East Asian (EAS)

AF:

0.00

AC:

AN:

39582

South Asian (SAS)

AF:

0.00

AC:

AN:

85408

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52314

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4934

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1110262

Other (OTH)

AF:

0.00

AC:

AN:

60112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.455

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

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

GnomAD4 genome

AF:

0.0000329

AC:

AN:

152144

Hom.:

Cov.:

AF XY:

0.0000538

AC XY:

AN XY:

74322

show subpopulations

African (AFR)

AF:

0.0000966

AC:

AN:

41424

American (AMR)

AF:

0.0000654

AC:

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5190

South Asian (SAS)

AF:

0.00

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10606

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68020

Other (OTH)

AF:

0.00

AC:

AN:

2090

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.405

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

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:

0.00

Hom.:

Bravo

AF:

0.0000378

ExAC

AF:

0.0000248

AC:

ClinVar

ClinVar submissions as Germline

Significance:Uncertain significance

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Inborn genetic diseases (1)

not provided (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.56

BayesDel_addAF

Benign

-0.33

BayesDel_noAF

Benign

-0.40

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.44

Eigen

Benign

-0.092

Eigen_PC

Benign

-0.22

FATHMM_MKL

Uncertain

0.86

LIST_S2

Uncertain

0.92

M_CAP

Uncertain

0.087

MetaRNN

Benign

0.17

MetaSVM

Benign

-1.1

PhyloP100

0.39

PrimateAI

Uncertain

0.66

PROVEAN

Uncertain

-3.3

REVEL

Benign

0.15

Sift

Uncertain

0.0010

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.54

MutPred

0.18

Gain of MoRF binding (P = 0.1282)

MVP

0.40

MPC

1.4

ClinPred

0.68

GERP RS

-2.1

PromoterAI

-0.027

Neutral

(source)

Varity_R

0.64

gMVP

0.30

Mutation Taster

=79/21

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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