NM_001904.4:c.1684-175C>T

Variant names:

• chr3-41235549-C-T
• rs11564465
• NM_001904.4:c.1684-175C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001904.4(CTNNB1):​c.1684-175C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.392 in 759,648 control chromosomes in the GnomAD database, including 62,667 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.33 (9883 hom., cov: 31)
  • Exomes 𝑓: 0.41 (52784 hom.)
• Consequence: CTNNB1 NM_001904.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.855
• Publications: 17 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 3-41235549-C-T is Benign according to our data. Variant chr3-41235549-C-T is described in ClinVar as Benign. ClinVar VariationId is 1223535.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.437 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CTNNB1	NM_001904.4	c.1684-175C>T		intron_variant	Intron 10 of 14	ENST00000349496.11	NP_001895.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CTNNB1	ENST00000349496.11	c.1684-175C>T		intron_variant	Intron 10 of 14	1	NM_001904.4	ENSP00000344456.5
CTNNB1	ENST00000645982.1	c.1684-175C>T		intron_variant	Intron 10 of 15			ENSP00000494845.1
CTNNB1	ENST00000715152.1	n.1684-175C>T		intron_variant	Intron 10 of 15			ENSP00000520353.1

Frequencies

GnomAD3 genomes AF: 0.334 AC: 50747 AN: 151832 Hom.: 9885 Cov.: 31

Gnomad AFR AF: 0.134

Gnomad AMI AF: 0.432

Gnomad AMR AF: 0.332

Gnomad ASJ AF: 0.370

Gnomad EAS AF: 0.225

Gnomad SAS AF: 0.357

Gnomad FIN AF: 0.455

Gnomad MID AF: 0.313

Gnomad NFE AF: 0.441

Gnomad OTH AF: 0.342

GnomAD4 exome AF: 0.406 AC: 246933 AN: 607698 Hom.: 52784 Cov.: 8 AF XY: 0.404 AC XY: 130486 AN XY: 322904

African (AFR) AF: 0.134 AC: 2231 AN: 16632

American (AMR) AF: 0.339 AC: 11176 AN: 32950

Ashkenazi Jewish (ASJ) AF: 0.370 AC: 6639 AN: 17948

East Asian (EAS) AF: 0.201 AC: 6397 AN: 31802

South Asian (SAS) AF: 0.353 AC: 20463 AN: 57978

European-Finnish (FIN) AF: 0.449 AC: 14489 AN: 32248

Middle Eastern (MID) AF: 0.346 AC: 840 AN: 2426

European-Non Finnish (NFE) AF: 0.448 AC: 172240 AN: 384080

Other (OTH) AF: 0.394 AC: 12458 AN: 31634

GnomAD4 genome AF: 0.334 AC: 50746 AN: 151950 Hom.: 9883 Cov.: 31 AF XY: 0.332 AC XY: 24685 AN XY: 74286

African (AFR) AF: 0.133 AC: 5525 AN: 41450

American (AMR) AF: 0.332 AC: 5065 AN: 15246

Ashkenazi Jewish (ASJ) AF: 0.370 AC: 1285 AN: 3470

East Asian (EAS) AF: 0.225 AC: 1162 AN: 5162

South Asian (SAS) AF: 0.356 AC: 1715 AN: 4816

European-Finnish (FIN) AF: 0.455 AC: 4800 AN: 10544

Middle Eastern (MID) AF: 0.310 AC: 91 AN: 294

European-Non Finnish (NFE) AF: 0.441 AC: 29992 AN: 67940

Other (OTH) AF: 0.339 AC: 717 AN: 2116

Alfa AF: 0.336 Hom.: 1492

Bravo AF: 0.316

Asia WGS AF: 0.311 AC: 1084 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jul 15, 2018

GeneDx

Significance: 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	-0.83
CADD	Benign	7.8
DANN	Benign	0.81
PhyloP100		-0.85
Mutation Taster		=100/0	polymorphism (auto)

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: rs11564465; hg19: chr3-41277040;