5-113043585-T-A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001085377.2(MCC):c.2701A>T(p.Arg901Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: MCC NM_001085377.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.742

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MCC	NM_001085377.2	c.2701A>T	p.Arg901Trp	missense_variant	17/19	ENST00000408903.7
MCC	NM_002387.3	c.2131A>T	p.Arg711Trp	missense_variant	15/17

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MCC	ENST00000408903.7	c.2701A>T	p.Arg901Trp	missense_variant	17/19	2	NM_001085377.2	P1
MCC	ENST00000302475.9	c.2131A>T	p.Arg711Trp	missense_variant	15/17	1
MCC	ENST00000515367.6	c.1942A>T	p.Arg648Trp	missense_variant	15/17	5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 12, 2023

The c.2701A>T (p.R901W) alteration is located in exon 17 (coding exon 17) of the MCC gene. This alteration results from a A to T substitution at nucleotide position 2701, causing the arginine (R) at amino acid position 901 to be replaced by a tryptophan (W). 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	Benign	0.21
BayesDel_addAF	Benign	0.0084	T
BayesDel_noAF	Benign	-0.23
Cadd	Benign	18
Dann	Uncertain	1.0
DEOGEN2	Benign	0.10	T;.;.
Eigen	Benign	-0.40
Eigen_PC	Benign	-0.53
FATHMM_MKL	Benign	0.59	D
LIST_S2	Uncertain	0.97	D;D;D
M_CAP	Benign	0.048	D
MetaRNN	Uncertain	0.66	D;D;D
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.69	N;.;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.67	T
PROVEAN	Benign	-1.3	N;N;N
REVEL	Benign	0.21
Sift	Uncertain	0.0010	D;D;D
Sift4G	Uncertain	0.010	D;D;D
Polyphen		0.95	P;.;D
Vest4		0.75
MutPred		0.31		Loss of disorder (P = 0.0565);.;.;
MVP		0.48
MPC		0.24
ClinPred		0.79	D
GERP RS		-0.54
Varity_R		0.30
gMVP		0.34

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr5-112379282;