Genetic Variant MUC22:p.Met49Ile (chr6-31025578-G-A) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_001395414.1(MUC22):c.147G>A(p.Met49Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000204 in 1,519,526 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000027 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000020 ( 0 hom. )

Consequence

MUC22
NM_001395414.1 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -6.33

Publications

0 publications found

Variant links:

Genes affected

MUC22 (HGNC:39755): (mucin 22) Predicted to be integral component of membrane. [provided by Alliance of Genome Resources, Apr 2022]

MUC22 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.05260274).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001395414.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
MUC22	NM_001395414.1	MANE Select	c.147G>A	p.Met49Ile	missense	Exon 2 of 4	NP_001382343.1	E2RYF6
MUC22	NM_001318484.1		c.156G>A	p.Met52Ile	missense	Exon 3 of 5	NP_001305413.1	E2RYF6
MUC22	NM_001198815.1		c.147G>A	p.Met49Ile	missense	Exon 3 of 5	NP_001185744.1	E2RYF6

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MUC22	ENST00000561890.1	TSL:2 MANE Select	c.147G>A	p.Met49Ile	missense	Exon 2 of 4	ENSP00000455906.1	E2RYF6

Frequencies

GnomAD3 genomes

AF:

0.0000267

AC:

AN:

149980

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000246

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000198

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:

0.00000792

AC:

AN:

126242

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000420

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:

0.0000197

AC:

AN:

1369546

Hom.:

Cov.:

AF XY:

0.0000104

AC XY:

AN XY:

675526

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

31202

American (AMR)

AF:

0.0000290

AC:

AN:

34434

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24768

East Asian (EAS)

AF:

0.00

AC:

AN:

34838

South Asian (SAS)

AF:

0.00

AC:

AN:

77794

European-Finnish (FIN)

AF:

0.00

AC:

AN:

33562

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5636

European-Non Finnish (NFE)

AF:

0.0000224

AC:

AN:

1070052

Other (OTH)

AF:

0.0000349

AC:

AN:

57260

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.410

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome 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

GnomAD4 genome

AF:

0.0000267

AC:

AN:

149980

Hom.:

Cov.:

AF XY:

0.0000409

AC XY:

AN XY:

73302

show subpopulations

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.0000246

AC:

AN:

40668

American (AMR)

AF:

0.000198

AC:

AN:

15128

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3442

East Asian (EAS)

AF:

0.00

AC:

AN:

5016

South Asian (SAS)

AF:

0.00

AC:

AN:

4694

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10514

Middle Eastern (MID)

AF:

0.00

AC:

AN:

298

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

67266

Other (OTH)

AF:

0.00

AC:

AN:

2052

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.0000000000164189), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.362

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.27

BayesDel_addAF

Benign

-0.45

BayesDel_noAF

Benign

-0.89

CADD

Benign

0.0060

(source)

DANN

Benign

0.38

DEOGEN2

Benign

0.0031

FATHMM_MKL

Benign

0.0025

LIST_S2

Benign

0.40

M_CAP

Benign

0.010

MetaRNN

Benign

0.053

MutationAssessor

Benign

0.0

PhyloP100

-6.3

PrimateAI

Benign

0.17

PROVEAN

Benign

-0.43

Sift

Benign

0.40

Sift4G

Benign

0.19

Vest4

0.064

MVP

0.040

GERP RS

-2.9

Varity_R

0.046

gMVP

0.022

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over