5-138756008-T-G

Variant names:

• chr5-138756008-T-G
• rs12653845
• NM_001903.5:c.-3+2498T>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001903.5(CTNNA1):​c.-3+2498T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0597 in 149,184 control chromosomes in the GnomAD database, including 361 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.060 (361 hom., cov: 25)
• Consequence: CTNNA1 NM_001903.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.297
• Publications: 2 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: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
• patterned macular dystrophy

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

  Inheritance: Unknown Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.122 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CTNNA1	NM_001903.5	MANE Select	c.-3+2498T>G		intron	N/A	NP_001894.2	A0A384MDY0
	CTNNA1	NM_001323982.2		c.-3+845T>G		intron	N/A	NP_001310911.1	P35221-1
	CTNNA1	NM_001323983.1		c.-3+1910T>G		intron	N/A	NP_001310912.1	A0A384MDY0

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CTNNA1	ENST00000302763.12	TSL:1 MANE Select	c.-3+2498T>G		intron	N/A	ENSP00000304669.7	P35221-1
	CTNNA1	ENST00000965845.1		c.-3+2498T>G		intron	N/A	ENSP00000635904.1
	CTNNA1	ENST00000930310.1		c.-3+2498T>G		intron	N/A	ENSP00000600369.1

Frequencies

GnomAD3 genomes AF: 0.0597 AC: 8902 AN: 149066 Hom.: 360 Cov.: 25

Gnomad AFR AF: 0.0191

Gnomad AMI AF: 0.00332

Gnomad AMR AF: 0.0799

Gnomad ASJ AF: 0.0902

Gnomad EAS AF: 0.130

Gnomad SAS AF: 0.121

Gnomad FIN AF: 0.0891

Gnomad MID AF: 0.137

Gnomad NFE AF: 0.0639

Gnomad OTH AF: 0.0814

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

GnomAD4 genome AF: 0.0597 AC: 8902 AN: 149184 Hom.: 361 Cov.: 25 AF XY: 0.0625 AC XY: 4544 AN XY: 72666

African (AFR) AF: 0.0192 AC: 776 AN: 40478

American (AMR) AF: 0.0797 AC: 1169 AN: 14666

Ashkenazi Jewish (ASJ) AF: 0.0902 AC: 311 AN: 3446

East Asian (EAS) AF: 0.130 AC: 655 AN: 5030

South Asian (SAS) AF: 0.121 AC: 561 AN: 4634

European-Finnish (FIN) AF: 0.0891 AC: 912 AN: 10238

Middle Eastern (MID) AF: 0.134 AC: 39 AN: 292

European-Non Finnish (NFE) AF: 0.0638 AC: 4306 AN: 67446

Other (OTH) AF: 0.0829 AC: 170 AN: 2050

Alfa AF: 0.0611 Hom.: 318

Bravo AF: 0.0588

Asia WGS AF: 0.154 AC: 534 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	1.1
DANN	Benign	0.47
PhyloP100		-0.30
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs12653845; hg19: chr5-138091697;