NM_001904.4:c.-48-3dupT

Variant names:

• chr3-41224011-C-CT
• rs968099699
• NM_001904.4:c.-48-3dupT

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PVS1_Moderate BS2

The NM_001904.4(CTNNB1):​c.-48-3dupT variant causes a splice acceptor, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000567 in 1,586,636 control chromosomes in the GnomAD database, with no homozygous occurrence. 1/1 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000056 (0 hom.)
• Consequence: CTNNB1 NM_001904.4 splice_acceptor, intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.109
• Publications: 0 publications found

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]

CTNNB1 Gene-Disease associations (from GenCC):

• exudative vitreoretinopathy

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, G2P
• severe intellectual disability-progressive spastic diplegia syndrome

  Inheritance: AD, Unknown Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, Orphanet, Labcorp Genetics (formerly Invitae), Illumina, G2P, Ambry Genetics
• exudative vitreoretinopathy 7

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.026001705 fraction of the gene. Cryptic splice site detected, with MaxEntScore 8.6, offset of 0 (no position change), new splice context is: tttgattaacttttttttAGggt. Cryptic site results in inframe change. If cryptic site found is not functional and variant results in exon loss, it results in frameshift change.
• BS2: High AC in GnomAdExome4 at 8 AD,Unknown gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CTNNB1	NM_001904.4	c.-48-3dupT		splice_acceptor_variant, intron_variant	Intron 1 of 14	ENST00000349496.11	NP_001895.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CTNNB1	ENST00000349496.11	c.-48-3dupT		splice_acceptor_variant, intron_variant	Intron 1 of 14	1	NM_001904.4	ENSP00000344456.5
CTNNB1	ENST00000645982.1	c.-48-3dupT		splice_acceptor_variant, intron_variant	Intron 1 of 15			ENSP00000494845.1
CTNNB1	ENST00000715152.1	n.-48-3dupT		splice_acceptor_variant, intron_variant	Intron 1 of 15			ENSP00000520353.1

Frequencies

GnomAD3 genomes AF: 0.00000658 AC: 1 AN: 152052 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000558 AC: 8 AN: 1434584 Hom.: 0 Cov.: 27 AF XY: 0.00000419 AC XY: 3 AN XY: 715660

African (AFR) AF: 0.00 AC: 0 AN: 32848

American (AMR) AF: 0.00 AC: 0 AN: 44584

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25938

East Asian (EAS) AF: 0.00 AC: 0 AN: 39562

South Asian (SAS) AF: 0.00 AC: 0 AN: 85728

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53404

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5692

European-Non Finnish (NFE) AF: 0.00000736 AC: 8 AN: 1087380

Other (OTH) AF: 0.00 AC: 0 AN: 59448

GnomAD4 genome AF: 0.00000658 AC: 1 AN: 152052 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74252

African (AFR) AF: 0.00 AC: 0 AN: 41408

American (AMR) AF: 0.00 AC: 0 AN: 15246

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5194

South Asian (SAS) AF: 0.00 AC: 0 AN: 4820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10590

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68004

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000151

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.11

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

Other links and lift over

dbSNP: rs968099699; hg19: chr3-41265502;