Genetic Variant MUC1:p.Thr22Thr (chr1-155192276-C-T) – ACMG Classification: Benign (-21 pts)

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_001371720.2(MUC1):c.93G>A(p.Thr31Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.555 in 1,613,186 control chromosomes in the GnomAD database, including 251,968 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.59 ( 26289 hom., cov: 32)

Exomes 𝑓: 0.55 ( 225679 hom. )

Consequence

MUC1
NM_001371720.2 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 0.0300

Publications

250 publications found

Variant links:

Genes affected

MUC1 (HGNC:7508): (mucin 1, cell surface associated) This gene encodes a membrane-bound protein 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. These proteins also play a role in intracellular signaling. This protein is expressed on the apical surface of epithelial cells that line the mucosal surfaces of many different tissues including lung, breast stomach and pancreas. This protein is proteolytically cleaved into alpha and beta subunits that form a heterodimeric complex. The N-terminal alpha subunit functions in cell-adhesion and the C-terminal beta subunit is involved in cell signaling. Overexpression, aberrant intracellular localization, and changes in glycosylation of this protein have been associated with carcinomas. This gene is known to contain a highly polymorphic variable number tandem repeats (VNTR) domain. Alternate splicing results in multiple transcript variants.[provided by RefSeq, Feb 2011]

MUC1 Gene-Disease associations (from GenCC):

tubulointerstitial kidney disease, autosomal dominant, 2
Inheritance: Unknown, AD Classification: DEFINITIVE, MODERATE, SUPPORTIVE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, Orphanet, Ambry Genetics

MUC1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_addAF=-0.812439).

BP6

Variant 1-155192276-C-T is Benign according to our data. Variant chr1-155192276-C-T is described in ClinVar as Benign. ClinVar VariationId is 1321177.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=0.03 with no splicing effect.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.76 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001371720.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
MUC1	NM_001371720.2	c.93G>A	p.Thr31Thr	synonymous	Exon 2 of 12	NP_001358649.2
MUC1	NM_001204286.1	c.93G>A	p.Thr31Thr	synonymous	Exon 2 of 8	NP_001191215.1	P15941
MUC1	NM_001204285.2	c.66G>A	p.Thr22Thr	synonymous	Exon 2 of 8	NP_001191214.1	A0A0C4DGW3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
MUC1	ENST00000620103.4	TSL:5	c.66G>A	p.Thr22Thr	synonymous	Exon 2 of 8	ENSP00000481231.1	A0A0C4DGW3
MUC1	ENST00000337604.6	TSL:1	c.66G>A	p.Thr22Thr	synonymous	Exon 2 of 8	ENSP00000338983.5	P15941-8
MUC1	ENST00000368392.7	TSL:1	c.93G>A	p.Thr31Thr	synonymous	Exon 2 of 8	ENSP00000357377.3	P15941-11

Frequencies

GnomAD3 genomes

AF:

0.586

AC:

88846

AN:

151722

Hom.:

26259

Cov.:

show subpopulations

Gnomad AFR

AF:

0.651

Gnomad AMI

AF:

0.422

Gnomad AMR

AF:

0.636

Gnomad ASJ

AF:

0.510

Gnomad EAS

AF:

0.781

Gnomad SAS

AF:

0.542

Gnomad FIN

AF:

0.563

Gnomad MID

AF:

0.513

Gnomad NFE

AF:

0.533

Gnomad OTH

AF:

0.577

GnomAD2 exomes

AF:

0.586

AC:

147016

AN:

251084

AF XY:

0.574

show subpopulations

Gnomad AFR exome

AF:

0.654

Gnomad AMR exome

AF:

0.706

Gnomad ASJ exome

AF:

0.515

Gnomad EAS exome

AF:

0.780

Gnomad FIN exome

AF:

0.562

Gnomad NFE exome

AF:

0.528

Gnomad OTH exome

AF:

0.562

GnomAD4 exome

AF:

0.552

AC:

806355

AN:

1461346

Hom.:

225679

Cov.:

AF XY:

0.549

AC XY:

398884

AN XY:

726988

show subpopulations

African (AFR)

AF:

0.651

AC:

21804

AN:

33468

American (AMR)

AF:

0.701

AC:

31312

AN:

44696

Ashkenazi Jewish (ASJ)

AF:

0.514

AC:

13429

AN:

26108

East Asian (EAS)

AF:

0.809

AC:

32125

AN:

39700

South Asian (SAS)

AF:

0.544

AC:

46964

AN:

86252

European-Finnish (FIN)

AF:

0.561

AC:

29904

AN:

53334

Middle Eastern (MID)

AF:

0.477

AC:

2750

AN:

5764

European-Non Finnish (NFE)

AF:

0.535

AC:

594525

AN:

1111656

Other (OTH)

AF:

0.556

AC:

33542

AN:

60368

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.480

Heterozygous variant carriers

21856

43711

65567

87422

109278

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

17178

34356

51534

68712

85890

<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:

0.586

AC:

88923

AN:

151840

Hom.:

26289

Cov.:

AF XY:

0.586

AC XY:

43445

AN XY:

74198

show subpopulations

African (AFR)

AF:

0.652

AC:

26937

AN:

41334

American (AMR)

AF:

0.637

AC:

9709

AN:

15244

Ashkenazi Jewish (ASJ)

AF:

0.510

AC:

1771

AN:

3472

East Asian (EAS)

AF:

0.781

AC:

4043

AN:

5180

South Asian (SAS)

AF:

0.541

AC:

2608

AN:

4820

European-Finnish (FIN)

AF:

0.563

AC:

5944

AN:

10560

Middle Eastern (MID)

AF:

0.514

AC:

151

AN:

294

European-Non Finnish (NFE)

AF:

0.533

AC:

36169

AN:

67916

Other (OTH)

AF:

0.572

AC:

1207

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.508

Heterozygous variant carriers

1937

3874

5812

7749

9686

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

738

1476

2214

2952

3690

<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:

0.552

Hom.:

104045

Bravo

AF:

0.600

TwinsUK

AF:

0.521

AC:

1933

ALSPAC

AF:

0.540

AC:

2083

ESP6500AA

AF:

0.644

AC:

2839

ESP6500EA

AF:

0.535

AC:

4605

ExAC

AF:

0.578

AC:

70180

Asia WGS

AF:

0.673

AC:

2341

AN:

3478

EpiCase

AF:

0.517

EpiControl

AF:

0.513

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (1)

Tubulointerstitial kidney disease, autosomal dominant, 2 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.81

BayesDel_noAF

Benign

-0.80

CADD

Benign

4.3

(source)

DANN

Benign

0.53

FATHMM_MKL

Benign

0.00046

PhyloP100

0.030

GERP RS

0.30

Mutation Taster

=100/0

polymorphism (auto)

(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