5-113071088-G-GCCTCGCGCTGTCTT

Variant names:

• chr5-113071088-G-GCCTCGCGCTGTCTT
• rs11283943
• NM_001085377.2:c.1925+5_1925+6insAAGACAGCGCGAGG

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP6_Moderate BA1

The NM_001085377.2(MCC):​c.1925+5_1925+6insAAGACAGCGCGAGG variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.335 in 1,599,818 control chromosomes in the GnomAD database, including 92,075 homozygotes. It is difficult to determine the true allele frequency of this variant because it is of type INS_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.34 (8767 hom., cov: 0)
  • Exomes 𝑓: 0.33 (83308 hom.)
• Consequence: MCC NM_001085377.2 splice_region, intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.14
• Publications: 10 publications found

Genes affected

MCC (HGNC:6935): (MCC regulator of WNT signaling pathway) This gene is a candidate colorectal tumor suppressor gene that is thought to negatively regulate cell cycle progression. The orthologous gene in the mouse expresses a phosphoprotein associated with the plasma membrane and membrane organelles, and overexpression of the mouse protein inhibits entry into S phase. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

ACMG classification

Our verdict: Benign. The variant received -10 ACMG points.

• BP6: Variant 5-113071088-G-GCCTCGCGCTGTCTT is Benign according to our data. Variant chr5-113071088-G-GCCTCGCGCTGTCTT is described in ClinVar as Benign. ClinVar VariationId is 769303.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.346 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MCC	NM_001085377.2	c.1925+5_1925+6insAAGACAGCGCGAGG		splice_region_variant, intron_variant	Intron 12 of 18	ENST00000408903.7	NP_001078846.2
MCC	NM_002387.3	c.1355+5_1355+6insAAGACAGCGCGAGG		splice_region_variant, intron_variant	Intron 10 of 16		NP_002378.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MCC	ENST00000408903.7	c.1925+5_1925+6insAAGACAGCGCGAGG		splice_region_variant, intron_variant	Intron 12 of 18	2	NM_001085377.2	ENSP00000386227.3
MCC	ENST00000302475.9	c.1355+5_1355+6insAAGACAGCGCGAGG		splice_region_variant, intron_variant	Intron 10 of 16	1		ENSP00000305617.4
MCC	ENST00000515367.6	c.1166+5_1166+6insAAGACAGCGCGAGG		splice_region_variant, intron_variant	Intron 10 of 16	5		ENSP00000421615.2
MCC	ENST00000514701.5	c.1355+5_1355+6insAAGACAGCGCGAGG		splice_region_variant, intron_variant	Intron 10 of 13	2		ENSP00000485220.1

Frequencies

GnomAD3 genomes AF: 0.340 AC: 51538 AN: 151726 Hom.: 8754 Cov.: 0

Gnomad AFR AF: 0.342

Gnomad AMI AF: 0.338

Gnomad AMR AF: 0.310

Gnomad ASJ AF: 0.320

Gnomad EAS AF: 0.318

Gnomad SAS AF: 0.363

Gnomad FIN AF: 0.372

Gnomad MID AF: 0.376

Gnomad NFE AF: 0.341

Gnomad OTH AF: 0.330

GnomAD2 exomes AF: 0.323 AC: 78358 AN: 242414 AF XY: 0.326

Gnomad AFR exome AF: 0.337

Gnomad AMR exome AF: 0.278

Gnomad ASJ exome AF: 0.308

Gnomad EAS exome AF: 0.303

Gnomad FIN exome AF: 0.363

Gnomad NFE exome AF: 0.325

Gnomad OTH exome AF: 0.320

GnomAD4 exome AF: 0.335 AC: 484637 AN: 1447974 Hom.: 83308 Cov.: 35 AF XY: 0.336 AC XY: 241969 AN XY: 720284

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.334 AC: 11059 AN: 33098

American (AMR) AF: 0.287 AC: 12657 AN: 44152

Ashkenazi Jewish (ASJ) AF: 0.322 AC: 8326 AN: 25864

East Asian (EAS) AF: 0.289 AC: 11380 AN: 39440

South Asian (SAS) AF: 0.354 AC: 29945 AN: 84648

European-Finnish (FIN) AF: 0.358 AC: 19001 AN: 53144

Middle Eastern (MID) AF: 0.325 AC: 1845 AN: 5676

European-Non Finnish (NFE) AF: 0.336 AC: 370636 AN: 1102086

Other (OTH) AF: 0.331 AC: 19788 AN: 59866

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.340 AC: 51583 AN: 151844 Hom.: 8767 Cov.: 0 AF XY: 0.341 AC XY: 25316 AN XY: 74184

African (AFR) AF: 0.342 AC: 14174 AN: 41390

American (AMR) AF: 0.310 AC: 4733 AN: 15260

Ashkenazi Jewish (ASJ) AF: 0.320 AC: 1111 AN: 3468

East Asian (EAS) AF: 0.318 AC: 1641 AN: 5160

South Asian (SAS) AF: 0.360 AC: 1735 AN: 4814

European-Finnish (FIN) AF: 0.372 AC: 3909 AN: 10506

Middle Eastern (MID) AF: 0.384 AC: 112 AN: 292

European-Non Finnish (NFE) AF: 0.341 AC: 23158 AN: 67940

Other (OTH) AF: 0.334 AC: 703 AN: 2106

Alfa AF: 0.270 Hom.: 1195

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Dec 31, 2019

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.1
Mutation Taster		=99/1	polymorphism (auto)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs11283943; hg19: chr5-112406785;