rs148289936

chr5-138933900-A-G

Variant summary

Our verdict is Benign. Variant got -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BP7 BS2

The NM_001903.5(CTNNA1):c.2532A>G(p.Gln844=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000774 in 1,614,162 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00040 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000044 (0 hom.)
• Consequence: CTNNA1 NM_001903.5 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 1.86

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 -17 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.66).
• BP6: Variant 5-138933900-A-G is Benign according to our data. Variant chr5-138933900-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 415356.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=1.86 with no splicing effect.
• BS2: High AC in GnomAd at 62 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CTNNA1	NM_001903.5	c.2532A>G	p.Gln844=	synonymous_variant	18/18	ENST00000302763.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CTNNA1	ENST00000302763.12	c.2532A>G	p.Gln844=	synonymous_variant	18/18	1	NM_001903.5	P1

Frequencies

GnomAD3 genomes AF: 0.000407 AC: 62 AN: 152150 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00140

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000479

GnomAD3 exomes AF: 0.000199 AC: 50 AN: 251458 Hom.: 0 AF XY: 0.000125 AC XY: 17 AN XY: 135916

Gnomad AFR exome AF: 0.00129

Gnomad AMR exome AF: 0.000694

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000131

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.0000438 AC: 64 AN: 1461894 Hom.: 0 Cov.: 31 AF XY: 0.0000330 AC XY: 24 AN XY: 727248

Gnomad4 AFR exome AF: 0.000747

Gnomad4 AMR exome AF: 0.000604

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000104

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000497

GnomAD4 genome AF: 0.000401 AC: 61 AN: 152268 Hom.: 0 Cov.: 32 AF XY: 0.000430 AC XY: 32 AN XY: 74472

Gnomad4 AFR AF: 0.00140

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.000474

Alfa AF: 0.000362 Hom.: 0

Bravo AF: 0.000563

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 22, 2024

- -

Hereditary cancer-predisposing syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 26, 2018

This alteration is classified as likely 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. -

CTNNA1-related condition Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 20, 2019

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.66
Cadd	Benign	5.4
Dann	Benign	0.48
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: rs148289936; hg19: chr5-138269589;