rs2953

Variant names:

• chr3-41239897-T-G
• rs2953
• NM_001904.4:c.*555T>G

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BA1

The NM_001904.4(CTNNB1):​c.*555T>G variant causes a 3 prime UTR change. The variant allele was found at a frequency of 0.422 in 211,094 control chromosomes in the GnomAD database, including 18,825 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.41 (12658 hom., cov: 28)
  • Exomes 𝑓: 0.45 (6167 hom.)
• Consequence: CTNNB1 NM_001904.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 5.19
• Publications: 46 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: G2P, Orphanet
• severe intellectual disability-progressive spastic diplegia syndrome

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

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

ACMG classification

Our verdict: Benign. The variant received -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.43).
• BP6: Variant 3-41239897-T-G is Benign according to our data. Variant chr3-41239897-T-G is described in ClinVar as Benign. ClinVar VariationId is 1235713.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.454 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001904.4. 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
	CTNNB1	NM_001904.4	MANE Select	c.*555T>G		3_prime_UTR	Exon 15 of 15	NP_001895.1	P35222
	CTNNB1	NM_001098209.2		c.*250T>G		3_prime_UTR	Exon 16 of 16	NP_001091679.1	P35222
	CTNNB1	NM_001098210.2		c.*91T>G		3_prime_UTR	Exon 16 of 16	NP_001091680.1	P35222

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CTNNB1	ENST00000349496.11	TSL:1 MANE Select	c.*555T>G		3_prime_UTR	Exon 15 of 15	ENSP00000344456.5	P35222
	CTNNB1	ENST00000396183.7	TSL:1	c.*91T>G		3_prime_UTR	Exon 16 of 16	ENSP00000379486.3	P35222
	CTNNB1	ENST00000396185.8	TSL:1	c.*250T>G		3_prime_UTR	Exon 16 of 16	ENSP00000379488.3	P35222

Frequencies

GnomAD3 genomes AF: 0.410 AC: 60907 AN: 148524 Hom.: 12657 Cov.: 28

Gnomad AFR AF: 0.346

Gnomad AMI AF: 0.435

Gnomad AMR AF: 0.373

Gnomad ASJ AF: 0.394

Gnomad EAS AF: 0.284

Gnomad SAS AF: 0.421

Gnomad FIN AF: 0.467

Gnomad MID AF: 0.374

Gnomad NFE AF: 0.458

Gnomad OTH AF: 0.405

GnomAD4 exome AF: 0.450 AC: 28143 AN: 62484 Hom.: 6167 Cov.: 0 AF XY: 0.451 AC XY: 13087 AN XY: 29012

African (AFR) AF: 0.367 AC: 1072 AN: 2918

American (AMR) AF: 0.378 AC: 768 AN: 2030

Ashkenazi Jewish (ASJ) AF: 0.424 AC: 1636 AN: 3854

East Asian (EAS) AF: 0.297 AC: 2590 AN: 8708

South Asian (SAS) AF: 0.458 AC: 260 AN: 568

European-Finnish (FIN) AF: 0.467 AC: 115 AN: 246

Middle Eastern (MID) AF: 0.405 AC: 153 AN: 378

European-Non Finnish (NFE) AF: 0.497 AC: 19199 AN: 38598

Other (OTH) AF: 0.453 AC: 2350 AN: 5184

GnomAD4 genome AF: 0.410 AC: 60924 AN: 148610 Hom.: 12658 Cov.: 28 AF XY: 0.406 AC XY: 29354 AN XY: 72260

African (AFR) AF: 0.346 AC: 14029 AN: 40582

American (AMR) AF: 0.373 AC: 5550 AN: 14896

Ashkenazi Jewish (ASJ) AF: 0.394 AC: 1352 AN: 3432

East Asian (EAS) AF: 0.285 AC: 1400 AN: 4916

South Asian (SAS) AF: 0.420 AC: 1929 AN: 4596

European-Finnish (FIN) AF: 0.467 AC: 4493 AN: 9630

Middle Eastern (MID) AF: 0.378 AC: 109 AN: 288

European-Non Finnish (NFE) AF: 0.458 AC: 30844 AN: 67320

Other (OTH) AF: 0.403 AC: 829 AN: 2056

Alfa AF: 0.445 Hom.: 17730

Bravo AF: 0.399

Asia WGS AF: 0.376 AC: 1311 AN: 3476

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.43
CADD	Benign	15
DANN	Benign	0.92
PhyloP100		5.2
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs2953; hg19: chr3-41281388;