Genetic Variant MUC17:p.Met226Ile (chr7-101032094-G-C) – ACMG Classification: Benign (-8 pts)

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_001040105.2(MUC17):c.678G>C(p.Met226Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000564 in 1,613,756 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.00011 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000051 ( 2 hom. )

Consequence

MUC17
NM_001040105.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -3.00

Variant links:

Genes affected

MUC17 (HGNC:16800): (mucin 17, cell surface associated) The protein encoded by this gene is a membrane-bound mucin that provides protection to gut epithelial cells. The encoded protein contains about 60 tandem repeats, with each repeat being around 60 aa. N-glycosylation enables the encoded protein to localize on the cell surface, while the C-terminus interacts with the scaffold protein PDZ domain containing 1 (PDZK1). Two transcript variants, one protein-coding and the other non-protein coding, have been found for this gene. [provided by RefSeq, Nov 2015]

MUC17 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.036040843).

BS2

High Homozygotes in GnomAdExome4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MUC17	NM_001040105.2 link	c.678G>C	p.Met226Ile	missense_variant	Exon 3 of 13	ENST00000306151.9	NP_001035194.1	Q685J3-1
MUC17	NR_133665.2 link	n.733G>C		non_coding_transcript_exon_variant	Exon 3 of 12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MUC17	ENST00000306151.9 link	c.678G>C	p.Met226Ile	missense_variant	Exon 3 of 13	1	NM_001040105.2	ENSP00000302716.4		Q685J3-1
MUC17	ENST00000379439.3 link	n.678G>C		non_coding_transcript_exon_variant	Exon 3 of 12	1		ENSP00000368751.3		E7EPM4

Frequencies

GnomAD3 genomes

AF:

0.0000988

AC:

AN:

151796

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000315

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000318

AC:

AN:

251360

Hom.:

AF XY:

0.0000368

AC XY:

AN XY:

135838

show subpopulations

Gnomad AFR exome

AF:

0.000308

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000176

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.0000513

AC:

AN:

1461838

Hom.:

Cov.:

AF XY:

0.0000605

AC XY:

AN XY:

727224

show subpopulations

Gnomad4 AFR exome

AF:

0.000777

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:

0.0000270

Gnomad4 OTH exome

AF:

0.000281

GnomAD4 genome

AF:

0.000105

AC:

AN:

151918

Hom.:

Cov.:

AF XY:

0.000108

AC XY:

AN XY:

74264

show subpopulations

Gnomad4 AFR

AF:

0.000338

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000435

Hom.:

Bravo

AF:

0.0000491

ExAC

AF:

0.0000330

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jan 24, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.678G>C (p.M226I) alteration is located in exon 3 (coding exon 3) of the MUC17 gene. This alteration results from a G to C substitution at nucleotide position 678, causing the methionine (M) at amino acid position 226 to be replaced by an isoleucine (I). 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

0.25

BayesDel_addAF

Benign

-0.63

BayesDel_noAF

Benign

-0.84

CADD

Benign

0.022

DANN

Benign

0.29

DEOGEN2

Benign

0.018

Eigen

Benign

-1.7

Eigen_PC

Benign

-1.8

FATHMM_MKL

Benign

0.00075

LIST_S2

Benign

0.42

M_CAP

Benign

0.00073

MetaRNN

Benign

0.036

MetaSVM

Benign

-0.92

MutationAssessor

Benign

0.69

PrimateAI

Benign

0.26

PROVEAN

Benign

-0.020

REVEL

Benign

0.0050

Sift

Benign

0.090

Polyphen

0.087

Vest4

0.050

MutPred

0.14

Gain of methylation at K227 (P = 0.0287);

MVP

0.030

ClinPred

0.018

GERP RS

-1.6

Varity_R

0.082

gMVP

0.0035

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over