rs11552054

chr5-138812254-A-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001903.5(CTNNA1):c.540A>C(p.Leu180=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0389 in 1,613,716 control chromosomes in the GnomAD database, including 1,508 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. L180L) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.028 (90 hom., cov: 32)
  • Exomes 𝑓: 0.040 (1418 hom.)
• Consequence: CTNNA1 NM_001903.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 1.04

Genes affected

CTNNA1 (HGNC:2509): (catenin alpha 1) This gene encodes a member of the catenin family of proteins that play an important role in cell adhesion process by connecting cadherins located on the plasma membrane to the actin filaments inside the cell. The encoded mechanosensing protein contains three vinculin homology domains and undergoes conformational changes in response to cytoskeletal tension, resulting in the reconfiguration of cadherin-actin filament connections. Certain mutations in this gene cause butterfly-shaped pigment dystrophy. [provided by RefSeq, May 2016]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.54).
• BP6: Variant 5-138812254-A-C is Benign according to our data. Variant chr5-138812254-A-C is described in ClinVar as [Benign]. Clinvar id is 415357.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-138812254-A-C is described in Lovd as [Benign].
• BA1: GnomAdExome4 highest subpopulation (MID) allele frequency at 95% confidence interval = 0.0698 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CTNNA1	NM_001903.5	c.540A>C	p.Leu180=	synonymous_variant	5/18	ENST00000302763.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CTNNA1	ENST00000302763.12	c.540A>C	p.Leu180=	synonymous_variant	5/18	1	NM_001903.5	P1

Frequencies

GnomAD3 genomes AF: 0.0279 AC: 4249 AN: 152174 Hom.: 90 Cov.: 32

Gnomad AFR AF: 0.00806

Gnomad AMI AF: 0.00439

Gnomad AMR AF: 0.0232

Gnomad ASJ AF: 0.0548

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.0523

Gnomad FIN AF: 0.0172

Gnomad MID AF: 0.0791

Gnomad NFE AF: 0.0420

Gnomad OTH AF: 0.0244

GnomAD3 exomes AF: 0.0323 AC: 8124 AN: 251314 Hom.: 191 AF XY: 0.0356 AC XY: 4833 AN XY: 135816

Gnomad AFR exome AF: 0.00812

Gnomad AMR exome AF: 0.0145

Gnomad ASJ exome AF: 0.0543

Gnomad EAS exome AF: 0.000381

Gnomad SAS exome AF: 0.0620

Gnomad FIN exome AF: 0.0151

Gnomad NFE exome AF: 0.0393

Gnomad OTH exome AF: 0.0393

GnomAD4 exome AF: 0.0400 AC: 58450 AN: 1461424 Hom.: 1418 Cov.: 31 AF XY: 0.0412 AC XY: 29961 AN XY: 727004

Gnomad4 AFR exome AF: 0.00720

Gnomad4 AMR exome AF: 0.0164

Gnomad4 ASJ exome AF: 0.0555

Gnomad4 EAS exome AF: 0.000176

Gnomad4 SAS exome AF: 0.0638

Gnomad4 FIN exome AF: 0.0191

Gnomad4 NFE exome AF: 0.0421

Gnomad4 OTH exome AF: 0.0378

GnomAD4 genome AF: 0.0279 AC: 4250 AN: 152292 Hom.: 90 Cov.: 32 AF XY: 0.0268 AC XY: 1995 AN XY: 74460

Gnomad4 AFR AF: 0.00804

Gnomad4 AMR AF: 0.0231

Gnomad4 ASJ AF: 0.0548

Gnomad4 EAS AF: 0.000579

Gnomad4 SAS AF: 0.0523

Gnomad4 FIN AF: 0.0172

Gnomad4 NFE AF: 0.0420

Gnomad4 OTH AF: 0.0241

Alfa AF: 0.0373 Hom.: 73

Bravo AF: 0.0264

Asia WGS AF: 0.0180 AC: 65 AN: 3478

EpiCase AF: 0.0446

EpiControl AF: 0.0402

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 22, 2018	- -

Hereditary cancer-predisposing syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 26, 2019

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.54
Cadd	Benign	8.5
Dann	Benign	0.74
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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

Publications

LitVar

Other links and lift over

dbSNP: rs11552054; hg19: chr5-138147943; COSMIC: COSV57077607; COSMIC: COSV57077607;