dbSNP rs1059110: CTNNA1:p.Ser740Ser (chr5-138930857-G-A) – ACMG Classification: Benign (-19 pts)

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BA1

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 (★★). Synonymous variant affecting the same amino acid position (i.e. S740S) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.31 ( 7853 hom., cov: 32)

Exomes 𝑓: 0.29 ( 63122 hom. )

Consequence

CTNNA1
NM_001903.5 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: -0.681

Publications

27 publications found

Variant links:

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]

CTNNA1 Gene-Disease associations (from GenCC):

CTNNA1-related diffuse gastric and lobular breast cancer syndrome
Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
patterned macular dystrophy 2
Inheritance: AD Classification: DEFINITIVE, STRONG, LIMITED Submitted by: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae)
patterned macular dystrophy
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
hereditary nonpolyposis colon cancer
Inheritance: Unknown Classification: NO_KNOWN Submitted by: ClinGen

CTNNA1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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 VariationId is 820919.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001903.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CTNNA1	NM_001903.5	MANE Select	c.2220G>A	p.Ser740Ser	synonymous	Exon 16 of 18	NP_001894.2	A0A384MDY0
CTNNA1	NM_001323982.2		c.2220G>A	p.Ser740Ser	synonymous	Exon 17 of 19	NP_001310911.1	P35221-1
CTNNA1	NM_001323983.1		c.2220G>A	p.Ser740Ser	synonymous	Exon 16 of 18	NP_001310912.1	A0A384MDY0

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CTNNA1	ENST00000302763.12	TSL:1 MANE Select	c.2220G>A	p.Ser740Ser	synonymous	Exon 16 of 18	ENSP00000304669.7	P35221-1
CTNNA1	ENST00000518825.5	TSL:1	c.2220G>A	p.Ser740Ser	synonymous	Exon 15 of 18	ENSP00000427821.1	G3XAM7
CTNNA1	ENST00000540387.5	TSL:1	c.1110G>A	p.Ser370Ser	synonymous	Exon 10 of 12	ENSP00000438476.1	P35221-3

Frequencies

GnomAD3 genomes

AF:

0.314

AC:

47726

AN:

151918

Hom.:

7835

Cov.:

show subpopulations

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

GnomAD2 exomes

AF:

0.274

AC:

68952

AN:

251416

AF XY:

0.273

show subpopulations

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 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.:

AF XY:

0.288

AC XY:

208685

AN XY:

725582

show subpopulations

African (AFR)

AF:

0.413

AC:

13766

AN:

33366

American (AMR)

AF:

0.268

AC:

11963

AN:

44716

Ashkenazi Jewish (ASJ)

AF:

0.328

AC:

8570

AN:

26112

East Asian (EAS)

AF:

0.00927

AC:

368

AN:

39698

South Asian (SAS)

AF:

0.263

AC:

22659

AN:

86166

European-Finnish (FIN)

AF:

0.304

AC:

16258

AN:

53416

Middle Eastern (MID)

AF:

0.267

AC:

1538

AN:

5764

European-Non Finnish (NFE)

AF:

0.295

AC:

326778

AN:

1108480

Other (OTH)

AF:

0.282

AC:

16976

AN:

60274

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.463

Heterozygous variant carriers

13429

26858

40288

53717

67146

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

10608

21216

31824

42432

53040

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.314

AC:

47784

AN:

152036

Hom.:

7853

Cov.:

AF XY:

0.309

AC XY:

22995

AN XY:

74328

show subpopulations

African (AFR)

AF:

0.407

AC:

16880

AN:

41454

American (AMR)

AF:

0.250

AC:

3820

AN:

15270

Ashkenazi Jewish (ASJ)

AF:

0.337

AC:

1171

AN:

3470

East Asian (EAS)

AF:

0.00637

AC:

AN:

5180

South Asian (SAS)

AF:

0.236

AC:

1137

AN:

4818

European-Finnish (FIN)

AF:

0.295

AC:

3119

AN:

10572

Middle Eastern (MID)

AF:

0.327

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.304

AC:

20643

AN:

67962

Other (OTH)

AF:

0.283

AC:

598

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1662

3324

4987

6649

8311

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

472

944

1416

1888

2360

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.302

Hom.:

11236

Bravo

AF:

0.312

Asia WGS

AF:

0.135

AC:

470

AN:

3478

EpiCase

AF:

0.294

EpiControl

AF:

0.283

ClinVar

ClinVar submissions as Germline

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Hereditary cancer-predisposing syndrome (2)

not provided (2)

Hereditary diffuse gastric adenocarcinoma (1)

Patterned macular dystrophy 2 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.32

CADD

Benign

3.7

(source)

DANN

Benign

0.62

PhyloP100

-0.68

PromoterAI

-0.045

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Mutation Taster

=96/4

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over