3-41224522-A-G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_001904.4(CTNNB1):​c.14-4A>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0014 in 1,612,842 control chromosomes in the GnomAD database, including 40 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0077 ( 23 hom., cov: 32)
Exomes 𝑓: 0.00075 ( 17 hom. )

Consequence

CTNNB1
NM_001904.4 splice_region, intron

Scores

2
Splicing: ADA: 0.0002925
2

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: -0.779
Variant links:
Genes affected
CTNNB1 (HGNC:2514): (catenin beta 1) The protein encoded by this gene is part of a complex of proteins that constitute adherens junctions (AJs). AJs are necessary for the creation and maintenance of epithelial cell layers by regulating cell growth and adhesion between cells. The encoded protein also anchors the actin cytoskeleton and may be responsible for transmitting the contact inhibition signal that causes cells to stop dividing once the epithelial sheet is complete. Finally, this protein binds to the product of the APC gene, which is mutated in adenomatous polyposis of the colon. Mutations in this gene are a cause of colorectal cancer (CRC), pilomatrixoma (PTR), medulloblastoma (MDB), and ovarian cancer. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Aug 2016]

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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=-0.73).
BP6
Variant 3-41224522-A-G is Benign according to our data. Variant chr3-41224522-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 128866.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BS1
Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00765 (1165/152252) while in subpopulation AFR AF = 0.0266 (1103/41540). AF 95% confidence interval is 0.0253. There are 23 homozygotes in GnomAd4. There are 527 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position FAILED quality control check.
BS2
High AC in GnomAd4 at 1165 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
CTNNB1NM_001904.4 linkc.14-4A>G splice_region_variant, intron_variant Intron 2 of 14 ENST00000349496.11 NP_001895.1 P35222A0A024R2Q3

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
CTNNB1ENST00000349496.11 linkc.14-4A>G splice_region_variant, intron_variant Intron 2 of 14 1 NM_001904.4 ENSP00000344456.5 P35222
CTNNB1ENST00000645982.1 linkc.14-4A>G splice_region_variant, intron_variant Intron 2 of 15 ENSP00000494845.1 P35222

Frequencies

GnomAD3 genomes
AF:
0.00768
AC:
1168
AN:
152132
Hom.:
24
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0267
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00308
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.000207
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000441
Gnomad OTH
AF:
0.00622
GnomAD2 exomes
AF:
0.00202
AC:
508
AN:
250872
AF XY:
0.00147
show subpopulations
Gnomad AFR exome
AF:
0.0278
Gnomad AMR exome
AF:
0.00122
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000353
Gnomad OTH exome
AF:
0.00147
GnomAD4 exome
AF:
0.000750
AC:
1096
AN:
1460590
Hom.:
17
Cov.:
31
AF XY:
0.000625
AC XY:
454
AN XY:
726684
show subpopulations
Gnomad4 AFR exome
AF:
0.0255
AC:
853
AN:
33442
Gnomad4 AMR exome
AF:
0.00164
AC:
73
AN:
44596
Gnomad4 ASJ exome
AF:
0.00
AC:
0
AN:
26124
Gnomad4 EAS exome
AF:
0.00
AC:
0
AN:
39688
Gnomad4 SAS exome
AF:
0.0000696
AC:
6
AN:
86206
Gnomad4 FIN exome
AF:
0.00
AC:
0
AN:
53400
Gnomad4 NFE exome
AF:
0.0000387
AC:
43
AN:
1111050
Gnomad4 Remaining exome
AF:
0.00191
AC:
115
AN:
60344
Heterozygous variant carriers
0
59
118
176
235
294
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
Exome Het
Exome Hom
Variant carriers
0
30
60
90
120
150
<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:
0.00765
AC:
1165
AN:
152252
Hom.:
23
Cov.:
32
AF XY:
0.00708
AC XY:
527
AN XY:
74438
show subpopulations
Gnomad4 AFR
AF:
0.0266
AC:
0.0265527
AN:
0.0265527
Gnomad4 AMR
AF:
0.00294
AC:
0.00294195
AN:
0.00294195
Gnomad4 ASJ
AF:
0.00
AC:
0
AN:
0
Gnomad4 EAS
AF:
0.00
AC:
0
AN:
0
Gnomad4 SAS
AF:
0.000207
AC:
0.000207297
AN:
0.000207297
Gnomad4 FIN
AF:
0.00
AC:
0
AN:
0
Gnomad4 NFE
AF:
0.0000441
AC:
0.0000441047
AN:
0.0000441047
Gnomad4 OTH
AF:
0.00616
AC:
0.0061553
AN:
0.0061553
Heterozygous variant carriers
0
58
115
173
230
288
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
Genome Het
Genome Hom
Variant carriers
0
20
40
60
80
100
<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:
0.00367
Hom.:
6
Bravo
AF:
0.00878
Asia WGS
AF:
0.00144
AC:
5
AN:
3476
EpiCase
AF:
0.000109
EpiControl
AF:
0.00

ClinVar

Significance: Benign/Likely benign
Submissions summary: Benign:4
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Benign:2
Oct 04, 2021
GeneDx
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Feb 03, 2025
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

not specified Benign:1
-
Genetic Services Laboratory, University of Chicago
Significance:Likely benign
Review Status:no assertion criteria provided
Collection Method:clinical testing

Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -

Medulloblastoma;C0206711:Pilomatrixoma;C0346629:Colorectal cancer;C0919267:Ovarian neoplasm;C2239176:Hepatocellular carcinoma;C3554449:Severe intellectual disability-progressive spastic diplegia syndrome;C4539767:Exudative vitreoretinopathy 7 Benign:1
May 13, 2022
Fulgent Genetics, Fulgent Genetics
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.73
CADD
Benign
1.6
DANN
Benign
0.73
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.0
Mutation Taster
=100/0
polymorphism (auto)

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Benign
0.00029
dbscSNV1_RF
Benign
0.068
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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs5743391; hg19: chr3-41266013; COSMIC: COSV62698765; API