rs28363462

Variant names:

• chr5-138917757-C-T
• rs28363462
• NM_001903.5:c.1405C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001324006.1(CTNNA1):​c.-45C>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00189 in 1,614,036 control chromosomes in the GnomAD database, including 50 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.011 (26 hom., cov: 33)
  • Exomes 𝑓: 0.00099 (24 hom.)
• Consequence: CTNNA1 NM_001324006.1 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -0.308
• Publications: 5 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.7).
• BP6: Variant 5-138917757-C-T is Benign according to our data. Variant chr5-138917757-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 415354.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0105 (1602/152294) while in subpopulation AFR AF = 0.0366 (1523/41568). AF 95% confidence interval is 0.0351. There are 26 homozygotes in GnomAd4. There are 751 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High AC in GnomAd4 at 1602 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001324006.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CTNNA1	NM_001903.5	MANE Select	c.1405C>T	p.Leu469Leu	synonymous	Exon 11 of 18	NP_001894.2
	CTNNA1	NM_001324006.1		c.-45C>T		5_prime_UTR_premature_start_codon_gain	Exon 9 of 16	NP_001310935.1
	CTNNA1	NM_001324007.1		c.-45C>T		5_prime_UTR_premature_start_codon_gain	Exon 8 of 15	NP_001310936.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CTNNA1	ENST00000302763.12	TSL:1 MANE Select	c.1405C>T	p.Leu469Leu	synonymous	Exon 11 of 18	ENSP00000304669.7
	CTNNA1	ENST00000518825.5	TSL:1	c.1405C>T	p.Leu469Leu	synonymous	Exon 10 of 18	ENSP00000427821.1
	CTNNA1	ENST00000540387.5	TSL:1	c.295C>T	p.Leu99Leu	synonymous	Exon 5 of 12	ENSP00000438476.1

Frequencies

GnomAD3 genomes AF: 0.0105 AC: 1593 AN: 152176 Hom.: 26 Cov.: 33

Gnomad AFR AF: 0.0365

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00360

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000118

Gnomad OTH AF: 0.00669

GnomAD2 exomes AF: 0.00272 AC: 683 AN: 251168 AF XY: 0.00195

Gnomad AFR exome AF: 0.0390

Gnomad AMR exome AF: 0.000955

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000106

Gnomad OTH exome AF: 0.000327

GnomAD4 exome AF: 0.000986 AC: 1441 AN: 1461742 Hom.: 24 Cov.: 30 AF XY: 0.000842 AC XY: 612 AN XY: 727174

African (AFR) AF: 0.0366 AC: 1223 AN: 33458

American (AMR) AF: 0.00110 AC: 49 AN: 44712

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26130

East Asian (EAS) AF: 0.00 AC: 0 AN: 39692

South Asian (SAS) AF: 0.0000928 AC: 8 AN: 86234

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53416

Middle Eastern (MID) AF: 0.00191 AC: 11 AN: 5768

European-Non Finnish (NFE) AF: 0.0000351 AC: 39 AN: 1111942

Other (OTH) AF: 0.00184 AC: 111 AN: 60390

GnomAD4 genome AF: 0.0105 AC: 1602 AN: 152294 Hom.: 26 Cov.: 33 AF XY: 0.0101 AC XY: 751 AN XY: 74464

African (AFR) AF: 0.0366 AC: 1523 AN: 41568

American (AMR) AF: 0.00353 AC: 54 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.000415 AC: 2 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10598

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.000118 AC: 8 AN: 68036

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

Alfa AF: 0.00618 Hom.: 7

Bravo AF: 0.0115

Asia WGS AF: 0.00173 AC: 6 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	Hereditary cancer-predisposing syndrome (1)
-	-	1	Hereditary diffuse gastric adenocarcinoma (1)
-	-	1	Hereditary nonpolyposis colon cancer (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.70
CADD	Benign	1.9
DANN	Benign	0.52
PhyloP100		-0.31
Mutation Taster		=97/3	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: rs28363462; hg19: chr5-138253446;