5-113043623-G-A

Position:

• chr5-113043623-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2 PP5 BP4

The NM_001085377.2(MCC):​c.2663C>T​(p.Ala888Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 34)
• Consequence: MCC NM_001085377.2 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 2.02

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

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 5-113043623-G-A is Pathogenic according to our data. Variant chr5-113043623-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 14202.Status of the report is no_assertion_criteria_provided, 0 stars.
• BP4: Computational evidence support a benign effect (MetaRNN=0.0753206). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MCC	NM_001085377.2	c.2663C>T	p.Ala888Val	missense_variant	17/19	ENST00000408903.7	NP_001078846.2
MCC	NM_002387.3	c.2093C>T	p.Ala698Val	missense_variant	15/17		NP_002378.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MCC	ENST00000408903.7	c.2663C>T	p.Ala888Val	missense_variant	17/19	2	NM_001085377.2	ENSP00000386227	P1
MCC	ENST00000302475.9	c.2093C>T	p.Ala698Val	missense_variant	15/17	1		ENSP00000305617
MCC	ENST00000515367.6	c.1904C>T	p.Ala635Val	missense_variant	15/17	5		ENSP00000421615

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 34

Alfa AF: 0.0000613 Hom.: 0

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Carcinoma of colon Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Mar 15, 1991

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.080
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.48
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Benign	0.083	T;.;.
Eigen	Benign	-0.66
Eigen_PC	Benign	-0.53
FATHMM_MKL	Benign	0.50	D
LIST_S2	Uncertain	0.91	D;D;D
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.075	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.55	N;.;.
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.40	T
PROVEAN	Benign	-0.55	N;N;N
REVEL	Benign	0.019
Sift	Benign	0.16	T;T;T
Sift4G	Benign	0.088	T;T;T
Polyphen		0.020	B;.;B
Vest4		0.21
MVP		0.32
MPC		0.081
ClinPred		0.14	T
GERP RS		3.5
Varity_R		0.055
gMVP		0.11

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs121917731; hg19: chr5-112379320;