5-138772249-A-G

Variant names:

• chr5-138772249-A-G
• rs537861449
• NM_001903.5:c.-2-9674A>G

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_001903.5(CTNNA1):​c.-2-9674A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00752 in 152,360 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (no stars).

• Frequency: Genomes: 𝑓 0.0075 (7 hom., cov: 32)
• Consequence: CTNNA1 NM_001903.5 intron
• Clinical Significance: Likely benign no assertion criteria provided B:1
• Conservation: PhyloP100: 0.428
• Publications: 0 publications found

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: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics
• patterned macular dystrophy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• hereditary nonpolyposis colon cancer

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.51).
• BP6: Variant 5-138772249-A-G is Benign according to our data. Variant chr5-138772249-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 223715.Status of the report is no_assertion_criteria_provided, 0 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00752 (1146/152360) while in subpopulation NFE AF = 0.0111 (755/68028). AF 95% confidence interval is 0.0104. There are 7 homozygotes in GnomAd4. There are 587 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 1146 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CTNNA1	NM_001903.5	c.-2-9674A>G		intron_variant	Intron 1 of 17	ENST00000302763.12	NP_001894.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CTNNA1	ENST00000302763.12	c.-2-9674A>G		intron_variant	Intron 1 of 17	1	NM_001903.5	ENSP00000304669.7

Frequencies

GnomAD3 genomes AF: 0.00753 AC: 1146 AN: 152242 Hom.: 7 Cov.: 32

Gnomad AFR AF: 0.00203

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00432

Gnomad ASJ AF: 0.0101

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00351

Gnomad FIN AF: 0.0165

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0111

Gnomad OTH AF: 0.00669

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.00752 AC: 1146 AN: 152360 Hom.: 7 Cov.: 32 AF XY: 0.00788 AC XY: 587 AN XY: 74510

African (AFR) AF: 0.00202 AC: 84 AN: 41590

American (AMR) AF: 0.00425 AC: 65 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.0101 AC: 35 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00372 AC: 18 AN: 4834

European-Finnish (FIN) AF: 0.0165 AC: 175 AN: 10628

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0111 AC: 755 AN: 68028

Other (OTH) AF: 0.00662 AC: 14 AN: 2114

Alfa AF: 0.00953 Hom.: 3

Bravo AF: 0.00671

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

Submissions by phenotype

Hereditary cancer-predisposing syndrome Benign:1

Dec 01, 2015

University of Washington Department of Laboratory Medicine, University of Washington

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.51
CADD	Benign	6.2
DANN	Benign	0.83
PhyloP100		0.43
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs537861449; hg19: chr5-138107938;