Genetic Variant MUC12:p.Arg1133Pro (chr7-100993961-G-C) – ACMG Classification: Benign (-8 pts)

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_001164462.2(MUC12):c.3398G>C(p.Arg1133Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000225 in 1,290,508 control chromosomes in the GnomAD database, including 8 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/22 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. R1133H) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00023 ( 6 hom., cov: 13)

Exomes 𝑓: 0.0000067 ( 2 hom. )

Consequence

MUC12
NM_001164462.2 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -1.69

Publications

7 publications found

Variant links:

Genes affected

MUC12 (HGNC:7510): (mucin 12, cell surface associated) This gene encodes an integral membrane glycoprotein that is a member of the mucin family. Mucins are O-glycosylated proteins that play an essential role in forming protective mucous barriers on epithelial surfaces and have been implicated in epithelial renewal and differentiation. These glycoproteins also play a role in intracellular signaling. This protein is expressed on the apical membrane surface of epithelial cells that line the mucosal surfaces of many different tissues including the colon, pancreas, prostate, and uterus. The expression of this gene is downregulated in colorectal cancer tissue. [provided by RefSeq, Apr 2017]

MUC12 links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.058499128).

BS2

High Homozygotes in GnomAd4 at 6 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001164462.2. 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
	MUC12	NM_001164462.2	MANE Select	c.3398G>C	p.Arg1133Pro	missense	Exon 2 of 12	NP_001157934.1	Q9UKN1-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
MUC12	ENST00000536621.6	TSL:5 MANE Select	c.3398G>C	p.Arg1133Pro	missense	Exon 2 of 12	ENSP00000441929.1	Q9UKN1-2
MUC12	ENST00000379442.7	TSL:5	c.3827G>C	p.Arg1276Pro	missense	Exon 5 of 15	ENSP00000368755.3	Q9UKN1-1
MUC12	ENST00000895813.1		c.68-12510G>C		intron	N/A	ENSP00000565872.1

Frequencies

GnomAD3 genomes

AF:

0.000228

AC:

AN:

92134

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000591

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000577

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000192

AC:

AN:

104196

AF XY:

0.0000181

show subpopulations

Gnomad AFR exome

AF:

0.000176

Gnomad AMR exome

AF:

0.0000479

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000668

AC:

AN:

1198374

Hom.:

Cov.:

AF XY:

0.00000169

AC XY:

AN XY:

592096

show subpopulations

African (AFR)

AF:

0.000254

AC:

AN:

27576

American (AMR)

AF:

0.0000302

AC:

AN:

33090

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

21488

East Asian (EAS)

AF:

0.00

AC:

AN:

26310

South Asian (SAS)

AF:

0.00

AC:

AN:

73118

European-Finnish (FIN)

AF:

0.00

AC:

AN:

26452

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4552

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

936772

Other (OTH)

AF:

0.00

AC:

AN:

49016

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000228

AC:

AN:

92134

Hom.:

Cov.:

AF XY:

0.000248

AC XY:

AN XY:

44422

show subpopulations

African (AFR)

AF:

0.000591

AC:

AN:

25396

American (AMR)

AF:

0.000577

AC:

AN:

10398

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2292

East Asian (EAS)

AF:

0.00

AC:

AN:

2634

South Asian (SAS)

AF:

0.00

AC:

AN:

2696

European-Finnish (FIN)

AF:

0.00

AC:

AN:

5436

Middle Eastern (MID)

AF:

0.00

AC:

AN:

226

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

41062

Other (OTH)

AF:

0.00

AC:

AN:

1354

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.508

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00

Hom.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.33

BayesDel_addAF

Benign

-0.54

BayesDel_noAF

Benign

-0.74

CADD

Benign

2.4

(source)

DANN

Benign

0.35

DEOGEN2

Benign

0.0039

Eigen

Benign

-1.4

Eigen_PC

Benign

-1.6

FATHMM_MKL

Benign

0.0012

LIST_S2

Benign

0.25

M_CAP

Benign

0.0061

MetaRNN

Benign

0.058

MetaSVM

Benign

-0.98

MutationAssessor

Benign

0.34

PhyloP100

-1.7

PrimateAI

Benign

0.45

PROVEAN

Benign

0.020

REVEL

Benign

0.0060

Sift

Benign

0.039

Sift4G

Benign

0.22

Vest4

0.11

MutPred

0.20

Gain of glycosylation at R1133 (P = 0.0143)

MVP

0.081

ClinPred

0.013

GERP RS

-1.4

Varity_R

0.11

gMVP

0.0017

Mutation Taster

=100/0

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over