NM_001903.5:c.2220G>A

Variant names:

• chr5-138930857-G-A
• rs1059110
• NM_001903.5:c.2220G>A

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_001903.5(CTNNA1):​c.2220G>A​(p.Ser740Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.29 in 1,610,028 control chromosomes in the GnomAD database, including 70,975 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.31 (7853 hom., cov: 32)
  • Exomes 𝑓: 0.29 (63122 hom.)
• Consequence: CTNNA1 NM_001903.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.681

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=-0.32).
• BP6: Variant 5-138930857-G-A is Benign according to our data. Variant chr5-138930857-G-A is described in ClinVar as [Benign]. Clinvar id is 820919.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-138930857-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-0.681 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.402 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CTNNA1	NM_001903.5	c.2220G>A	p.Ser740Ser	synonymous_variant	Exon 16 of 18	ENST00000302763.12	NP_001894.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CTNNA1	ENST00000302763.12	c.2220G>A	p.Ser740Ser	synonymous_variant	Exon 16 of 18	1	NM_001903.5	ENSP00000304669.7

Frequencies

GnomAD3 genomes AF: 0.314 AC: 47726 AN: 151918 Hom.: 7835 Cov.: 32

Gnomad AFR AF: 0.407

Gnomad AMI AF: 0.317

Gnomad AMR AF: 0.251

Gnomad ASJ AF: 0.337

Gnomad EAS AF: 0.00616

Gnomad SAS AF: 0.237

Gnomad FIN AF: 0.295

Gnomad MID AF: 0.316

Gnomad NFE AF: 0.304

Gnomad OTH AF: 0.288

GnomAD3 exomes AF: 0.274 AC: 68952 AN: 251416 Hom.: 10445 AF XY: 0.273 AC XY: 37033 AN XY: 135894

Gnomad AFR exome AF: 0.406

Gnomad AMR exome AF: 0.271

Gnomad ASJ exome AF: 0.323

Gnomad EAS exome AF: 0.00299

Gnomad SAS exome AF: 0.259

Gnomad FIN exome AF: 0.298

Gnomad NFE exome AF: 0.295

Gnomad OTH exome AF: 0.275

GnomAD4 exome AF: 0.287 AC: 418876 AN: 1457992 Hom.: 63122 Cov.: 31 AF XY: 0.288 AC XY: 208685 AN XY: 725582

Gnomad4 AFR exome AF: 0.413

Gnomad4 AMR exome AF: 0.268

Gnomad4 ASJ exome AF: 0.328

Gnomad4 EAS exome AF: 0.00927

Gnomad4 SAS exome AF: 0.263

Gnomad4 FIN exome AF: 0.304

Gnomad4 NFE exome AF: 0.295

Gnomad4 OTH exome AF: 0.282

GnomAD4 genome AF: 0.314 AC: 47784 AN: 152036 Hom.: 7853 Cov.: 32 AF XY: 0.309 AC XY: 22995 AN XY: 74328

Gnomad4 AFR AF: 0.407

Gnomad4 AMR AF: 0.250

Gnomad4 ASJ AF: 0.337

Gnomad4 EAS AF: 0.00637

Gnomad4 SAS AF: 0.236

Gnomad4 FIN AF: 0.295

Gnomad4 NFE AF: 0.304

Gnomad4 OTH AF: 0.283

Alfa AF: 0.298 Hom.: 8893

Bravo AF: 0.312

Asia WGS AF: 0.135 AC: 470 AN: 3478

EpiCase AF: 0.294

EpiControl AF: 0.283

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 22, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary cancer-predisposing syndrome Benign:1

Nov 08, 2018

Ambry Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Nov 13, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

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	-0.32
CADD	Benign	3.7
DANN	Benign	0.62
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1059110; hg19: chr5-138266546; COSMIC: COSV57072058; COSMIC: COSV57072058;