Genetic Variant MCC:p.Ala911Thr (chr5-113043555-C-T) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001085377.2(MCC):c.2731G>A(p.Ala911Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,778 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A911S) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

MCC
NM_001085377.2 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.52

Publications

0 publications found

Variant links:

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]

MCC links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.08803609).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MCC	NM_001085377.2 link	c.2731G>A	p.Ala911Thr	missense_variant	Exon 17 of 19	ENST00000408903.7	NP_001078846.2	P23508-2
MCC	NM_002387.3 link	c.2161G>A	p.Ala721Thr	missense_variant	Exon 15 of 17		NP_002378.2	P23508-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
MCC	ENST00000408903.7 link	c.2731G>A	p.Ala911Thr	missense_variant	Exon 17 of 19	2	NM_001085377.2	ENSP00000386227.3	P23508-2
MCC	ENST00000302475.9 link	c.2161G>A	p.Ala721Thr	missense_variant	Exon 15 of 17	1		ENSP00000305617.4	P23508-1
MCC	ENST00000515367.6 link	c.1972G>A	p.Ala658Thr	missense_variant	Exon 15 of 17	5		ENSP00000421615.2	D6REY2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461778

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727186

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44702

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26134

East Asian (EAS)

AF:

0.00

AC:

AN:

39698

South Asian (SAS)

AF:

0.00

AC:

AN:

86222

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53402

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

8.99e-7

AC:

AN:

1111980

Other (OTH)

AF:

0.00

AC:

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.077

BayesDel_addAF

Benign

-0.22

BayesDel_noAF

Benign

-0.55

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.082

T;.;.

Eigen

Benign

-0.70

Eigen_PC

Benign

-0.58

FATHMM_MKL

Benign

0.57

LIST_S2

Benign

0.86

D;D;D

M_CAP

Benign

0.015

MetaRNN

Benign

0.088

T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.69

N;.;.

PhyloP100

1.5

PrimateAI

Benign

0.37

PROVEAN

Benign

-0.27

N;N;N

REVEL

Benign

0.030

Sift

Benign

0.34

T;T;T

Sift4G

Benign

0.80

T;T;T

Polyphen

0.11

B;.;B

Vest4

0.12

MutPred

0.21

Loss of helix (P = 0.0444);.;.;

MVP

0.26

MPC

0.076

ClinPred

0.20

GERP RS

3.4

Varity_R

0.033

gMVP

0.064

Mutation Taster

=88/12

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over