NM_001904.4:c.2077-67A>G

Variant names:

• chr3-41237949-A-G
• rs4135385
• NM_001904.4:c.2077-67A>G

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.2077-67A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.234 in 1,341,932 control chromosomes in the GnomAD database, including 41,069 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.19 (3718 hom., cov: 32)
  • Exomes 𝑓: 0.24 (37351 hom.)
• Consequence: CTNNB1 NM_001904.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.93
• Publications: 54 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=-0.79).
• BP6: Variant 3-41237949-A-G is Benign according to our data. Variant chr3-41237949-A-G is described in ClinVar as Benign. ClinVar VariationId is 1276603.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.519 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.2077-67A>G		intron	N/A	NP_001895.1
	CTNNB1	NM_001098209.2		c.2077-67A>G		intron	N/A	NP_001091679.1
	CTNNB1	NM_001098210.2		c.2077-67A>G		intron	N/A	NP_001091680.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CTNNB1	ENST00000349496.11	TSL:1 MANE Select	c.2077-67A>G		intron	N/A	ENSP00000344456.5
	CTNNB1	ENST00000396183.7	TSL:1	c.2077-67A>G		intron	N/A	ENSP00000379486.3
	CTNNB1	ENST00000396185.8	TSL:1	c.2077-67A>G		intron	N/A	ENSP00000379488.3

Frequencies

GnomAD3 genomes AF: 0.192 AC: 29226 AN: 151962 Hom.: 3703 Cov.: 32

Gnomad AFR AF: 0.0499

Gnomad AMI AF: 0.144

Gnomad AMR AF: 0.257

Gnomad ASJ AF: 0.229

Gnomad EAS AF: 0.535

Gnomad SAS AF: 0.206

Gnomad FIN AF: 0.188

Gnomad MID AF: 0.172

Gnomad NFE AF: 0.237

Gnomad OTH AF: 0.203

GnomAD4 exome AF: 0.240 AC: 284973 AN: 1189852 Hom.: 37351 Cov.: 16 AF XY: 0.239 AC XY: 144789 AN XY: 605686

African (AFR) AF: 0.0385 AC: 1089 AN: 28304

American (AMR) AF: 0.304 AC: 13432 AN: 44252

Ashkenazi Jewish (ASJ) AF: 0.233 AC: 5677 AN: 24396

East Asian (EAS) AF: 0.530 AC: 20351 AN: 38386

South Asian (SAS) AF: 0.206 AC: 16594 AN: 80674

European-Finnish (FIN) AF: 0.206 AC: 10969 AN: 53128

Middle Eastern (MID) AF: 0.203 AC: 1071 AN: 5266

European-Non Finnish (NFE) AF: 0.235 AC: 203524 AN: 864354

Other (OTH) AF: 0.240 AC: 12266 AN: 51092

GnomAD4 genome AF: 0.192 AC: 29246 AN: 152080 Hom.: 3718 Cov.: 32 AF XY: 0.193 AC XY: 14329 AN XY: 74336

African (AFR) AF: 0.0498 AC: 2066 AN: 41502

American (AMR) AF: 0.257 AC: 3931 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.229 AC: 795 AN: 3470

East Asian (EAS) AF: 0.536 AC: 2760 AN: 5152

South Asian (SAS) AF: 0.207 AC: 1001 AN: 4830

European-Finnish (FIN) AF: 0.188 AC: 1987 AN: 10574

Middle Eastern (MID) AF: 0.161 AC: 47 AN: 292

European-Non Finnish (NFE) AF: 0.237 AC: 16093 AN: 67970

Other (OTH) AF: 0.206 AC: 435 AN: 2110

Alfa AF: 0.224 Hom.: 8878

Bravo AF: 0.194

Asia WGS AF: 0.306 AC: 1063 AN: 3478

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	-0.79
CADD	Benign	1.6
DANN	Benign	0.84
PhyloP100		-1.9
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: rs4135385; hg19: chr3-41279440; COSMIC: COSV62693727; COSMIC: COSV62693727;