5-113027396-T-C

Variant names:

• chr5-113027396-T-C
• rs1028116706
• NM_001085377.2:c.2966A>G

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 1P and 0B. PP3

The NM_001085377.2(MCC):​c.2966A>G​(p.Glu989Gly) variant causes a missense change. The variant allele was found at a frequency of 0.00000929 in 1,614,088 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000053 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000048 (0 hom.)
• Consequence: MCC NM_001085377.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.10
• Publications: 0 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: Uncertain_significance. The variant received 1 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.783

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MCC	NM_001085377.2	c.2966A>G	p.Glu989Gly	missense_variant	Exon 19 of 19	ENST00000408903.7	NP_001078846.2
MCC	NM_002387.3	c.2396A>G	p.Glu799Gly	missense_variant	Exon 17 of 17		NP_002378.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MCC	ENST00000408903.7	c.2966A>G	p.Glu989Gly	missense_variant	Exon 19 of 19	2	NM_001085377.2	ENSP00000386227.3
MCC	ENST00000302475.9	c.2396A>G	p.Glu799Gly	missense_variant	Exon 17 of 17	1		ENSP00000305617.4
MCC	ENST00000515367.6	c.2207A>G	p.Glu736Gly	missense_variant	Exon 17 of 17	5		ENSP00000421615.2

Frequencies

GnomAD3 genomes AF: 0.0000526 AC: 8 AN: 152210 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000523

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000479 AC: 7 AN: 1461878 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727240

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.0000894 AC: 4 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111998

Other (OTH) AF: 0.0000497 AC: 3 AN: 60394

GnomAD4 genome AF: 0.0000526 AC: 8 AN: 152210 Hom.: 0 Cov.: 32 AF XY: 0.0000672 AC XY: 5 AN XY: 74350

African (AFR) AF: 0.00 AC: 0 AN: 41448

American (AMR) AF: 0.000523 AC: 8 AN: 15284

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5200

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68042

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.000246

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Aug 13, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2966A>G (p.E989G) alteration is located in exon 19 (coding exon 19) of the MCC gene. This alteration results from a A to G substitution at nucleotide position 2966, causing the glutamic acid (E) at amino acid position 989 to be replaced by a glycine (G). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.59
BayesDel_addAF	Pathogenic	0.27	D
BayesDel_noAF	Pathogenic	0.15
CADD	Pathogenic	27
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.23	T;.;.
Eigen	Uncertain	0.65
Eigen_PC	Pathogenic	0.68
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Uncertain	0.96	D;D;D
M_CAP	Benign	0.046	D
MetaRNN	Pathogenic	0.78	D;D;D
MetaSVM	Benign	-0.58	T
MutationAssessor	Benign	1.2	L;.;.
PhyloP100		6.1
PrimateAI	Pathogenic	0.85	D
PROVEAN	Uncertain	-2.5	D;D;N
REVEL	Uncertain	0.48
Sift	Uncertain	0.0080	D;D;D
Sift4G	Uncertain	0.012	D;D;D
Polyphen		0.99	D;.;D
Vest4		0.84
MutPred		0.53		Gain of loop (P = 0.0045);.;.;
MVP		0.69
MPC		0.47
ClinPred		0.94	D
GERP RS		5.8
Varity_R		0.23
gMVP		0.51
Mutation Taster		=75/25	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
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: rs1028116706; hg19: chr5-112363093;