5-113027411-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_001085377.2(MCC):c.2951T>C(p.Met984Thr) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,890 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 (no stars).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: MCC NM_001085377.2 missense
• Clinical Significance: Uncertain significance no assertion criteria provided U:1
• Conservation: PhyloP100: 7.08

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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.815

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MCC	NM_001085377.2	c.2951T>C	p.Met984Thr	missense_variant	19/19	ENST00000408903.7
MCC	NM_002387.3	c.2381T>C	p.Met794Thr	missense_variant	17/17

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MCC	ENST00000408903.7	c.2951T>C	p.Met984Thr	missense_variant	19/19	2	NM_001085377.2	P1
MCC	ENST00000302475.9	c.2381T>C	p.Met794Thr	missense_variant	17/17	1
MCC	ENST00000515367.6	c.2192T>C	p.Met731Thr	missense_variant	17/17	5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461890 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727244

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: no assertion criteria provided

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, no assertion criteria provided

literature only

Richard Lifton Laboratory, Yale University School of Medicine

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.77
BayesDel_addAF	Pathogenic	0.25	D
BayesDel_noAF	Uncertain	0.13
Cadd	Uncertain	23
Dann	Benign	0.96
DEOGEN2	Benign	0.41	T;.;.
Eigen	Uncertain	0.57
Eigen_PC	Uncertain	0.62
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.91	D;D;D
M_CAP	Benign	0.037	D
MetaRNN	Pathogenic	0.81	D;D;D
MetaSVM	Benign	-0.83	T
MutationAssessor	Benign	0.95	L;.;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Pathogenic	0.88	D
PROVEAN	Uncertain	-3.1	D;D;D
REVEL	Uncertain	0.39
Sift	Benign	0.13	T;T;T
Sift4G	Benign	0.17	T;T;T
Polyphen		0.84	P;.;P
Vest4		0.89
MutPred		0.63		Loss of stability (P = 0.1726);.;.;
MVP		0.68
MPC		0.39
ClinPred		0.95	D
GERP RS		5.8
Varity_R		0.36
gMVP		0.46

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

LitVar

Other links and lift over

dbSNP: rs386352328; hg19: chr5-112363108;