rs11552052

chr5-138930863-C-Gchr5-138930863-C-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_001903.5(CTNNA1):c.2226C>G(p.Val742=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0228 in 1,613,280 control chromosomes in the GnomAD database, including 550 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. V742V) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.020 (37 hom., cov: 32)
  • Exomes 𝑓: 0.023 (513 hom.)
• Consequence: CTNNA1 NM_001903.5 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.121

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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.39).
• BP6: Variant 5-138930863-C-G is Benign according to our data. Variant chr5-138930863-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 224932.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-138930863-C-G is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=0.121 with no splicing effect.
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.0196 (2993/152326) while in subpopulation AMR AF= 0.0296 (453/15304). AF 95% confidence interval is 0.0274. There are 37 homozygotes in gnomad4. There are 1425 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd at 2994 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CTNNA1	NM_001903.5	c.2226C>G	p.Val742=	synonymous_variant	16/18	ENST00000302763.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CTNNA1	ENST00000302763.12	c.2226C>G	p.Val742=	synonymous_variant	16/18	1	NM_001903.5	P1

Frequencies

GnomAD3 genomes AF: 0.0197 AC: 2994 AN: 152208 Hom.: 37 Cov.: 32

Gnomad AFR AF: 0.00466

Gnomad AMI AF: 0.0669

Gnomad AMR AF: 0.0296

Gnomad ASJ AF: 0.0317

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00228

Gnomad FIN AF: 0.0226

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.0275

Gnomad OTH AF: 0.0244

GnomAD3 exomes AF: 0.0198 AC: 4984 AN: 251464 Hom.: 74 AF XY: 0.0197 AC XY: 2681 AN XY: 135902

Gnomad AFR exome AF: 0.00486

Gnomad AMR exome AF: 0.0168

Gnomad ASJ exome AF: 0.0286

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00294

Gnomad FIN exome AF: 0.0232

Gnomad NFE exome AF: 0.0288

Gnomad OTH exome AF: 0.0269

GnomAD4 exome AF: 0.0232 AC: 33835 AN: 1460954 Hom.: 513 Cov.: 30 AF XY: 0.0226 AC XY: 16425 AN XY: 726866

Gnomad4 AFR exome AF: 0.00433

Gnomad4 AMR exome AF: 0.0177

Gnomad4 ASJ exome AF: 0.0276

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00285

Gnomad4 FIN exome AF: 0.0240

Gnomad4 NFE exome AF: 0.0263

Gnomad4 OTH exome AF: 0.0215

GnomAD4 genome AF: 0.0196 AC: 2993 AN: 152326 Hom.: 37 Cov.: 32 AF XY: 0.0191 AC XY: 1425 AN XY: 74488

Gnomad4 AFR AF: 0.00464

Gnomad4 AMR AF: 0.0296

Gnomad4 ASJ AF: 0.0317

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00228

Gnomad4 FIN AF: 0.0226

Gnomad4 NFE AF: 0.0275

Gnomad4 OTH AF: 0.0241

Alfa AF: 0.0240 Hom.: 15

Bravo AF: 0.0201

Asia WGS AF: 0.00202 AC: 7 AN: 3478

EpiCase AF: 0.0289

EpiControl AF: 0.0296

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	May 21, 2021	- -

Hereditary cancer-predisposing syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

May 08, 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. -

Patterned macular dystrophy 2 Benign:1

Benign, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Nov 09, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.39
Cadd	Benign	8.6
Dann	Benign	0.71
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs11552052; hg19: chr5-138266552; COSMIC: COSV57071184; COSMIC: COSV57071184;