rs186236339

Variant names:

• chr5-138824525-T-C
• rs186236339
• NM_001903.5:c.589-5T>C

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.589-5T>C variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00303 in 1,612,304 control chromosomes in the GnomAD database, including 21 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0019 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0031 (20 hom.)
• Consequence: CTNNA1 NM_001903.5 splice_region, intron
• Scores: Splicing: ADA: 0.003529
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:13
• Conservation: PhyloP100: 1.46
• Publications: 1 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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.72).
• BP6: Variant 5-138824525-T-C is Benign according to our data. Variant chr5-138824525-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 239066.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00193 (294/152326) while in subpopulation NFE AF = 0.00357 (243/68032). AF 95% confidence interval is 0.0032. There are 1 homozygotes in GnomAd4. There are 132 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 294 AD,Unknown gene.

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.589-5T>C		splice_region intron	N/A	NP_001894.2	A0A384MDY0
	CTNNA1	NM_001323982.2		c.589-5T>C		splice_region intron	N/A	NP_001310911.1	P35221-1
	CTNNA1	NM_001323983.1		c.589-5T>C		splice_region 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.589-5T>C		splice_region intron	N/A	ENSP00000304669.7	P35221-1
	CTNNA1	ENST00000518825.5	TSL:1	c.589-5T>C		splice_region intron	N/A	ENSP00000427821.1	G3XAM7
	CTNNA1	ENST00000518919.1	TSL:1	n.345-5T>C		splice_region intron	N/A

Frequencies

GnomAD3 genomes AF: 0.00193 AC: 294 AN: 152208 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000410

Gnomad AMI AF: 0.00329

Gnomad AMR AF: 0.000982

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00113

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00357

Gnomad OTH AF: 0.000957

GnomAD2 exomes AF: 0.00179 AC: 449 AN: 250726 AF XY: 0.00182

Gnomad AFR exome AF: 0.000615

Gnomad AMR exome AF: 0.00101

Gnomad ASJ exome AF: 0.00199

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00139

Gnomad NFE exome AF: 0.00303

Gnomad OTH exome AF: 0.00163

GnomAD4 exome AF: 0.00315 AC: 4595 AN: 1459978 Hom.: 20 Cov.: 31 AF XY: 0.00305 AC XY: 2215 AN XY: 725910

African (AFR) AF: 0.000509 AC: 17 AN: 33418

American (AMR) AF: 0.00107 AC: 48 AN: 44682

Ashkenazi Jewish (ASJ) AF: 0.00123 AC: 32 AN: 26088

East Asian (EAS) AF: 0.00 AC: 0 AN: 39626

South Asian (SAS) AF: 0.0000696 AC: 6 AN: 86224

European-Finnish (FIN) AF: 0.00122 AC: 65 AN: 53398

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5752

European-Non Finnish (NFE) AF: 0.00388 AC: 4307 AN: 1110470

Other (OTH) AF: 0.00199 AC: 120 AN: 60320

GnomAD4 genome AF: 0.00193 AC: 294 AN: 152326 Hom.: 1 Cov.: 32 AF XY: 0.00177 AC XY: 132 AN XY: 74490

African (AFR) AF: 0.000409 AC: 17 AN: 41572

American (AMR) AF: 0.000981 AC: 15 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5194

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4820

European-Finnish (FIN) AF: 0.00113 AC: 12 AN: 10624

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

European-Non Finnish (NFE) AF: 0.00357 AC: 243 AN: 68032

Other (OTH) AF: 0.000947 AC: 2 AN: 2112

Alfa AF: 0.00300 Hom.: 2

Bravo AF: 0.00192

EpiCase AF: 0.00398

EpiControl AF: 0.00267

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	5	not provided (5)
-	-	3	not specified (3)
-	1	1	Hereditary cancer-predisposing syndrome (2)
-	-	2	Patterned macular dystrophy 2 (2)
-	-	1	CTNNA1-related disorder (1)
-	-	1	Hereditary diffuse gastric adenocarcinoma (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.72
CADD	Benign	12
DANN	Benign	0.71
PhyloP100		1.5
Mutation Taster		=98/2	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0035
dbscSNV1_RF	Benign	0.022
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: rs186236339; hg19: chr5-138160214; COSMIC: COSV104406595;