rs62626346

Variant names:

• chr5-112835173-T-C
• rs62626346
• NM_000038.6:c.1958+8T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000038.6(APC):​c.1958+8T>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 0.00366 in 1,602,474 control chromosomes in the GnomAD database, including 128 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 Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0058 (19 hom., cov: 32)
  • Exomes 𝑓: 0.0034 (109 hom.)
• Consequence: APC NM_000038.6 splice_region, intron
• Scores: Splicing: ADA: 0.0002136
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:18 O:1
• Conservation: PhyloP100: -0.407
• Publications: 9 publications found

Genes affected

APC (HGNC:583): (APC regulator of WNT signaling pathway) This gene encodes a tumor suppressor protein that acts as an antagonist of the Wnt signaling pathway. It is also involved in other processes including cell migration and adhesion, transcriptional activation, and apoptosis. Defects in this gene cause familial adenomatous polyposis (FAP), an autosomal dominant pre-malignant disease that usually progresses to malignancy. Mutations in the APC gene have been found to occur in most colorectal cancers, where disease-associated mutations tend to be clustered in a small region designated the mutation cluster region (MCR) and result in a truncated protein product. [provided by RefSeq, Jun 2022]

APC Gene-Disease associations (from GenCC):

• classic or attenuated familial adenomatous polyposis

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• desmoid tumor

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Genomics England PanelApp
• familial adenomatous polyposis 1

  Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Ambry Genetics
• gastric adenocarcinoma and proximal polyposis of the stomach

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), ClinGen, Orphanet
• sarcoma

  Inheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp
• APC-related attenuated familial adenomatous polyposis

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Turcot syndrome with polyposis

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Cenani-Lenz syndactyly syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000258864 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.78).
• BP6: Variant 5-112835173-T-C is Benign according to our data. Variant chr5-112835173-T-C is described in ClinVar as Benign. ClinVar VariationId is 82616.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0743 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000038.6. 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
	APC	NM_000038.6	MANE Select	c.1958+8T>C		splice_region intron	N/A	NP_000029.2
	APC	NM_001407446.1		c.2042+8T>C		splice_region intron	N/A	NP_001394375.1
	APC	NM_001354896.2		c.2012+8T>C		splice_region intron	N/A	NP_001341825.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	APC	ENST00000257430.9	TSL:5 MANE Select	c.1958+8T>C		splice_region intron	N/A	ENSP00000257430.4
	APC	ENST00000508376.6	TSL:1	c.1958+8T>C		splice_region intron	N/A	ENSP00000427089.2
	APC	ENST00000502371.3	TSL:1	n.*156+8T>C		splice_region intron	N/A	ENSP00000484935.2

Frequencies

GnomAD3 genomes AF: 0.00578 AC: 880 AN: 152190 Hom.: 19 Cov.: 32

Gnomad AFR AF: 0.00577

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00183

Gnomad ASJ AF: 0.00288

Gnomad EAS AF: 0.0803

Gnomad SAS AF: 0.00228

Gnomad FIN AF: 0.000471

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00229

Gnomad OTH AF: 0.00624

GnomAD2 exomes AF: 0.00797 AC: 1911 AN: 239770 AF XY: 0.00748

Gnomad AFR exome AF: 0.00647

Gnomad AMR exome AF: 0.00106

Gnomad ASJ exome AF: 0.00222

Gnomad EAS exome AF: 0.0841

Gnomad FIN exome AF: 0.000471

Gnomad NFE exome AF: 0.00194

Gnomad OTH exome AF: 0.00506

GnomAD4 exome AF: 0.00343 AC: 4972 AN: 1450166 Hom.: 109 Cov.: 28 AF XY: 0.00346 AC XY: 2500 AN XY: 721684

African (AFR) AF: 0.00551 AC: 182 AN: 33030

American (AMR) AF: 0.00108 AC: 48 AN: 44270

Ashkenazi Jewish (ASJ) AF: 0.00257 AC: 67 AN: 26030

East Asian (EAS) AF: 0.0641 AC: 2514 AN: 39210

South Asian (SAS) AF: 0.00155 AC: 132 AN: 85326

European-Finnish (FIN) AF: 0.000752 AC: 40 AN: 53190

Middle Eastern (MID) AF: 0.00486 AC: 28 AN: 5760

European-Non Finnish (NFE) AF: 0.00152 AC: 1680 AN: 1103386

Other (OTH) AF: 0.00469 AC: 281 AN: 59964

GnomAD4 genome AF: 0.00582 AC: 886 AN: 152308 Hom.: 19 Cov.: 32 AF XY: 0.00602 AC XY: 448 AN XY: 74468

African (AFR) AF: 0.00592 AC: 246 AN: 41568

American (AMR) AF: 0.00183 AC: 28 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.00288 AC: 10 AN: 3470

East Asian (EAS) AF: 0.0807 AC: 418 AN: 5182

South Asian (SAS) AF: 0.00207 AC: 10 AN: 4830

European-Finnish (FIN) AF: 0.000471 AC: 5 AN: 10612

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

European-Non Finnish (NFE) AF: 0.00229 AC: 156 AN: 68042

Other (OTH) AF: 0.00570 AC: 12 AN: 2104

Alfa AF: 0.00352 Hom.: 3

Bravo AF: 0.00631

Asia WGS AF: 0.0230 AC: 79 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	8	not specified (8)
-	-	3	Familial adenomatous polyposis 1 (3)
-	-	3	Hereditary cancer-predisposing syndrome (3)
-	-	2	not provided (2)
-	-	1	APC-Associated Polyposis Disorders (1)
-	-	1	Carcinoma of colon (1)
-	-	-	Familial colorectal cancer (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	5.6
DANN	Benign	0.79
PhyloP100		-0.41
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00021
dbscSNV1_RF	Benign	0.13
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: rs62626346; hg19: chr5-112170870; COSMIC: COSV57373884;