rs150893072

chr5-138824559-G-C

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 1P and 16B. PP2 BP4_Strong BP6_Very_Strong BS2

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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q206E) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0040 (5 hom., cov: 32)
  • Exomes 𝑓: 0.0045 (33 hom.)
• Consequence: CTNNA1 NM_001903.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 0.809

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 -15 ACMG points.

• PP2: Missense variant where missense usually causes diseases, CTNNA1
• 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 GnomAd at 605 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CTNNA1	NM_001903.5	c.618G>C	p.Gln206His	missense_variant	6/18	ENST00000302763.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CTNNA1	ENST00000302763.12	c.618G>C	p.Gln206His	missense_variant	6/18	1	NM_001903.5	P1

Frequencies

GnomAD3 genomes AF: 0.00397 AC: 605 AN: 152202 Hom.: 5 Cov.: 32

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.: 13 AF XY: 0.00439 AC XY: 596 AN XY: 135820

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.: 33 Cov.: 31 AF XY: 0.00439 AC XY: 3192 AN XY: 727218

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.: 5 Cov.: 32 AF XY: 0.00397 AC XY: 296 AN XY: 74480

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.: 0

Bravo AF: 0.00292

TwinsUK AF: 0.00512 AC: 19

ALSPAC AF: 0.00467 AC: 18

ESP6500AA AF: 0.00136 AC: 6

ESP6500EA AF: 0.00453 AC: 39

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

Submissions by phenotype

not provided Benign:4

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) -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Dec 01, 2022	CTNNA1: BS2 -

CTNNA1-related disorder Benign:1

Benign, criteria provided, single submitter

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	T
BayesDel_noAF	Benign	-0.27
Cadd	Benign	21
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	D
LIST_S2	Uncertain	0.96	D;D;D;D;.
MetaRNN	Benign	0.011	T;T;T;T;T
MetaSVM	Benign	-0.99	T
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.61	T
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	T
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

Other links and lift over

dbSNP: rs150893072; hg19: chr5-138160248;