chr5-113028982-C-T

Variant names:

• chr5-113028982-C-T
• rs746735411
• NM_001085377.2:c.2831G>A

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_001085377.2(MCC):​c.2831G>A​(p.Arg944Gln) variant causes a missense change. The variant allele was found at a frequency of 0.0000116 in 1,461,758 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: not found (cov: 31)
  • Exomes 𝑓: 0.000012 (0 hom.)
• Consequence: MCC NM_001085377.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.30
• 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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.752

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001085377.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MCC	NM_001085377.2	MANE Select	c.2831G>A	p.Arg944Gln	missense	Exon 18 of 19	NP_001078846.2	P23508-2
	MCC	NM_002387.3		c.2261G>A	p.Arg754Gln	missense	Exon 16 of 17	NP_002378.2	P23508-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MCC	ENST00000408903.7	TSL:2 MANE Select	c.2831G>A	p.Arg944Gln	missense	Exon 18 of 19	ENSP00000386227.3	P23508-2
	MCC	ENST00000302475.9	TSL:1	c.2261G>A	p.Arg754Gln	missense	Exon 16 of 17	ENSP00000305617.4	P23508-1
	MCC	ENST00000515367.6	TSL:5	c.2072G>A	p.Arg691Gln	missense	Exon 16 of 17	ENSP00000421615.2	D6REY2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.0000116 AC: 17 AN: 1461758 Hom.: 0 Cov.: 31 AF XY: 0.0000138 AC XY: 10 AN XY: 727178

African (AFR) AF: 0.00 AC: 0 AN: 33470

American (AMR) AF: 0.00 AC: 0 AN: 44710

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39694

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86236

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53404

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.0000126 AC: 14 AN: 1111952

Other (OTH) AF: 0.0000331 AC: 2 AN: 60394

GnomAD4 genome Cov.: 31

Alfa AF: 0.00 Hom.: 0

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.52
BayesDel_addAF	Uncertain	0.10	D
BayesDel_noAF	Benign	-0.090
CADD	Pathogenic	31
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.15	T
Eigen	Uncertain	0.66
Eigen_PC	Pathogenic	0.67
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Benign	0.034	D
MetaRNN	Pathogenic	0.75	D
MetaSVM	Benign	-0.77	T
MutationAssessor	Benign	1.5	L
PhyloP100		6.3
PrimateAI	Uncertain	0.73	T
PROVEAN	Benign	-1.9	N
REVEL	Benign	0.22
Sift	Uncertain	0.0050	D
Sift4G	Benign	0.085	T
Polyphen		1.0	D
Vest4		0.76
MutPred		0.53		Loss of MoRF binding (P = 0.0463)
MVP		0.69
MPC		0.46
ClinPred		0.81	D
GERP RS		5.6
Varity_R		0.32
gMVP		0.49
Mutation Taster		=53/47	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs746735411; hg19: chr5-112364679;