5-138930863-C-G

Variant names:

• chr5-138930863-C-G
• rs11552052
• NM_001903.5:c.2226C>G

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_001903.5(CTNNA1):​c.2226C>G​(p.Val742Val) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0228 in 1,613,280 control chromosomes in the GnomAD database, including 550 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. V742V) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.020 (37 hom., cov: 32)
  • Exomes 𝑓: 0.023 (513 hom.)
• Consequence: CTNNA1 NM_001903.5 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 0.121
• Publications: 9 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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.39).
• BP6: Variant 5-138930863-C-G is Benign according to our data. Variant chr5-138930863-C-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 224932.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.121 with no splicing effect.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.0196 (2993/152326) while in subpopulation AMR AF = 0.0296 (453/15304). AF 95% confidence interval is 0.0274. There are 37 homozygotes in GnomAd4. There are 1425 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 2993 AD 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.2226C>G	p.Val742Val	synonymous	Exon 16 of 18	NP_001894.2	A0A384MDY0
	CTNNA1	NM_001323982.2		c.2226C>G	p.Val742Val	synonymous	Exon 17 of 19	NP_001310911.1	P35221-1
	CTNNA1	NM_001323983.1		c.2226C>G	p.Val742Val	synonymous	Exon 16 of 18	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.2226C>G	p.Val742Val	synonymous	Exon 16 of 18	ENSP00000304669.7	P35221-1
	CTNNA1	ENST00000518825.5	TSL:1	c.2226C>G	p.Val742Val	synonymous	Exon 15 of 18	ENSP00000427821.1	G3XAM7
	CTNNA1	ENST00000540387.5	TSL:1	c.1116C>G	p.Val372Val	synonymous	Exon 10 of 12	ENSP00000438476.1	P35221-3

Frequencies

GnomAD3 genomes AF: 0.0197 AC: 2994 AN: 152208 Hom.: 37 Cov.: 32

Gnomad AFR AF: 0.00466

Gnomad AMI AF: 0.0669

Gnomad AMR AF: 0.0296

Gnomad ASJ AF: 0.0317

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00228

Gnomad FIN AF: 0.0226

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.0275

Gnomad OTH AF: 0.0244

GnomAD2 exomes AF: 0.0198 AC: 4984 AN: 251464 AF XY: 0.0197

Gnomad AFR exome AF: 0.00486

Gnomad AMR exome AF: 0.0168

Gnomad ASJ exome AF: 0.0286

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0232

Gnomad NFE exome AF: 0.0288

Gnomad OTH exome AF: 0.0269

GnomAD4 exome AF: 0.0232 AC: 33835 AN: 1460954 Hom.: 513 Cov.: 30 AF XY: 0.0226 AC XY: 16425 AN XY: 726866

African (AFR) AF: 0.00433 AC: 145 AN: 33454

American (AMR) AF: 0.0177 AC: 792 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.0276 AC: 722 AN: 26132

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39694

South Asian (SAS) AF: 0.00285 AC: 246 AN: 86240

European-Finnish (FIN) AF: 0.0240 AC: 1282 AN: 53420

Middle Eastern (MID) AF: 0.0186 AC: 107 AN: 5766

European-Non Finnish (NFE) AF: 0.0263 AC: 29242 AN: 1111156

Other (OTH) AF: 0.0215 AC: 1298 AN: 60370

GnomAD4 genome AF: 0.0196 AC: 2993 AN: 152326 Hom.: 37 Cov.: 32 AF XY: 0.0191 AC XY: 1425 AN XY: 74488

African (AFR) AF: 0.00464 AC: 193 AN: 41580

American (AMR) AF: 0.0296 AC: 453 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.0317 AC: 110 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5174

South Asian (SAS) AF: 0.00228 AC: 11 AN: 4826

European-Finnish (FIN) AF: 0.0226 AC: 240 AN: 10616

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.0275 AC: 1870 AN: 68032

Other (OTH) AF: 0.0241 AC: 51 AN: 2116

Alfa AF: 0.0240 Hom.: 15

Bravo AF: 0.0201

Asia WGS AF: 0.00202 AC: 7 AN: 3478

EpiCase AF: 0.0289

EpiControl AF: 0.0296

ClinVar

ClinVar submissions

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)
-	-	1	Patterned macular dystrophy 2 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.39
CADD	Benign	8.6
DANN	Benign	0.71
PhyloP100		0.12
PromoterAI		-0.029	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=89/11	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs11552052; hg19: chr5-138266552; COSMIC: COSV57071184;