rs150893072

Positions:

chr5-138824559-G-C

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 1P and 16B. PP2BP4_StrongBP6_Very_StrongBS2

The NM_001903.5(CTNNA1):c.618G>C(p.Gln206His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00441 in 1,614,158 control chromosomes in the GnomAD database, including 38 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0040 ( 5 hom., cov: 32)

Exomes 𝑓: 0.0045 ( 33 hom. )

Consequence

CTNNA1
NM_001903.5 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: 0.809

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 links:

CTNNA1 (HGNC:):

CTNNA1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -15 ACMG points.

PP2

Missense variant in gene, where missense usually causes diseases (based on misZ statistic), CTNNA1. . Gene score misZ 3.6624 (greater than the threshold 3.09). Trascript score misZ 4.1669 (greater than threshold 3.09). GenCC has associacion of gene with patterned macular dystrophy 2, CTNNA1-related diffuse gastric and lobular breast cancer syndrome, patterned macular dystrophy, hereditary nonpolyposis colon cancer.

BP4

Computational evidence support a benign effect (MetaRNN=0.011279106).

BP6

Variant 5-138824559-G-C is Benign according to our data. Variant chr5-138824559-G-C is described in ClinVar as [Likely_benign]. Clinvar id is 239067.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-138824559-G-C is described in Lovd as [Likely_benign]. Variant chr5-138824559-G-C is described in Lovd as [Benign].

BS2

High AC in GnomAd4 at 605 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CTNNA1	NM_001903.5 linkuse as main transcript	c.618G>C	p.Gln206His	missense_variant	6/18	ENST00000302763.12	NP_001894.2	P35221-1A0A384MDY0

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CTNNA1	ENST00000302763.12 linkuse as main transcript	c.618G>C	p.Gln206His	missense_variant	6/18	1	NM_001903.5	ENSP00000304669.7		P35221-1

Frequencies

GnomAD3 genomes

AF:

0.00397

AC:

605

AN:

152202

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00104

Gnomad AMI

AF:

0.00110

Gnomad AMR

AF:

0.00399

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0186

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00439

Gnomad OTH

AF:

0.00191

GnomAD3 exomes

AF:

0.00462

AC:

1160

AN:

251306

Hom.:

AF XY:

0.00439

AC XY:

596

AN XY:

135820

show subpopulations

Gnomad AFR exome

AF:

0.00111

Gnomad AMR exome

AF:

0.00168

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.0184

Gnomad NFE exome

AF:

0.00569

Gnomad OTH exome

AF:

0.00619

GnomAD4 exome

AF:

0.00445

AC:

6508

AN:

1461840

Hom.:

Cov.:

AF XY:

0.00439

AC XY:

3192

AN XY:

727218

show subpopulations

Gnomad4 AFR exome

AF:

0.000687

Gnomad4 AMR exome

AF:

0.00165

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000580

Gnomad4 FIN exome

AF:

0.0192

Gnomad4 NFE exome

AF:

0.00464

Gnomad4 OTH exome

AF:

0.00359

GnomAD4 genome

AF:

0.00397

AC:

605

AN:

152318

Hom.:

Cov.:

AF XY:

0.00397

AC XY:

296

AN XY:

74480

show subpopulations

Gnomad4 AFR

AF:

0.00103

Gnomad4 AMR

AF:

0.00399

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.0186

Gnomad4 NFE

AF:

0.00439

Gnomad4 OTH

AF:

0.00189

Alfa

AF:

0.00351

Hom.:

Bravo

AF:

0.00292

TwinsUK

AF:

0.00512

AC:

ALSPAC

AF:

0.00467

AC:

ESP6500AA

AF:

0.00136

AC:

ESP6500EA

AF:

0.00453

AC:

ExAC

AF:

0.00451

AC:

547

EpiCase

AF:

0.00360

EpiControl

AF:

0.00445

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:4

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Sep 01, 2024	CTNNA1: BS2 -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Likely benign, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	The CTNNA1 p.Gln206His variant was identified in 1 of 572 proband chromosomes (frequency: 0.00175) from European families with diffuse gastric cancer (Weren_2018_PMID:29330337). The variant was identified in dbSNP (ID: rs150893072), ClinVar (classified as benign by Invitae), and LOVD 3.0. The variant was also identified in control databases in 1298 of 282710 chromosomes (13 homozygous) at a frequency of 0.004591 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: European (Finnish) in 448 of 25122 chromosomes (freq: 0.01783), Other in 44 of 7224 chromosomes (freq: 0.006091), European (non-Finnish) in 723 of 129042 chromosomes (freq: 0.005603), Latino in 59 of 35424 chromosomes (freq: 0.001666), African in 23 of 24968 chromosomes (freq: 0.000921), South Asian in 1 of 30612 chromosomes (freq: 0.000033), while the variant was not observed in the Ashkenazi Jewish or East Asian populations. The p.Gln206 residue is conserved in mammals but not in more distantly related organisms, however four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and two of four in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign. -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 30, 2021	This variant is associated with the following publications: (PMID: 11997091, 29177109) -

CTNNA1-related disorder

Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 22, 2019

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

Hereditary cancer-predisposing syndrome

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 14, 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. -

Patterned macular dystrophy 2

Benign:1

Benign, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Oct 11, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.38

BayesDel_addAF

Benign

-0.35

BayesDel_noAF

Benign

-0.27

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.021

T;T;T;.;T

Eigen

Benign

0.028

Eigen_PC

Benign

0.070

FATHMM_MKL

Uncertain

0.95

LIST_S2

Uncertain

0.96

D;D;D;D;.

MetaRNN

Benign

0.011

T;T;T;T;T

MetaSVM

Benign

-0.99

MutationAssessor

Benign

1.8

.;L;.;.;.

PrimateAI

Uncertain

0.61

PROVEAN

Benign

-1.7

.;N;N;N;N

REVEL

Benign

0.15

Sift

Uncertain

0.0060

.;D;D;D;D

Sift4G

Uncertain

0.010

D;D;D;D;D

Polyphen

0.85

P;P;.;.;P

Vest4

0.68

MutPred

0.69

Loss of MoRF binding (P = 0.0964);Loss of MoRF binding (P = 0.0964);.;Loss of MoRF binding (P = 0.0964);Loss of MoRF binding (P = 0.0964);

MVP

0.51

MPC

0.19

ClinPred

0.021

GERP RS

2.3

Varity_R

0.68

gMVP

0.48

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over