Genetic Variant MUC15:p.Ser46Trp (chr11-26565803-G-C) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_001135091.2(MUC15):c.137C>G(p.Ser46Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00175 in 1,611,388 control chromosomes in the GnomAD database, including 48 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0094 ( 26 hom., cov: 33)

Exomes 𝑓: 0.00096 ( 22 hom. )

Consequence

MUC15
NM_001135091.2 missense

Scores

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: -0.0450

Publications

4 publications found

Variant links:

Genes affected

MUC15 (HGNC:14956): (mucin 15, cell surface associated) Predicted to be located in Golgi lumen and plasma membrane. [provided by Alliance of Genome Resources, Apr 2022]

MUC15 links:

ANO3 (HGNC:14004): (anoctamin 3) The protein encoded by this gene belongs to the TMEM16 family of predicted membrane proteins, that are also known as anoctamins. While little is known about the function of this gene, mutations in this gene have been associated with some cases of autosomal dominant craniocervical dystonia. Cells from individuals with a mutation in this gene exhibited abnormalities in endoplasmic reticulum-dependent calcium signaling. Studies in rat show that the rat ortholog of this protein interacts with, and modulates the activity of a sodium-activated potassium channel. Deletion of this gene caused increased pain sensitivity in the rat model system. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Aug 2015]

ANO3 Gene-Disease associations (from GenCC):

dystonia 24
Inheritance: AD Classification: STRONG, SUPPORTIVE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, G2P, Orphanet

ANO3 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0045607984).

BP6

Variant 11-26565803-G-C is Benign according to our data. Variant chr11-26565803-G-C is described in ClinVar as Likely_benign. ClinVar VariationId is 235242.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00941 (1415/150294) while in subpopulation AFR AF = 0.032 (1324/41326). AF 95% confidence interval is 0.0306. There are 26 homozygotes in GnomAd4. There are 681 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 26 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001135091.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
MUC15	NM_001135091.2	MANE Select	c.137C>G	p.Ser46Trp	missense	Exon 3 of 5	NP_001128563.1	A0A0A0MT67
ANO3	NM_031418.4	MANE Select	c.1447+6024G>C		intron	N/A	NP_113606.2	Q9BYT9-1
MUC15	NM_145650.4		c.56C>G	p.Ser19Trp	missense	Exon 2 of 4	NP_663625.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
MUC15	ENST00000529533.6	TSL:1 MANE Select	c.137C>G	p.Ser46Trp	missense	Exon 3 of 5	ENSP00000431983.1	A0A0A0MT67
MUC15	ENST00000527569.1	TSL:1	c.137C>G	p.Ser46Trp	missense	Exon 3 of 4	ENSP00000431945.1	A0A0A0MTD6
ANO3	ENST00000256737.8	TSL:1 MANE Select	c.1447+6024G>C		intron	N/A	ENSP00000256737.3	Q9BYT9-1

Frequencies

GnomAD3 genomes

AF:

0.00940

AC:

1412

AN:

150176

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0321

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00444

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000208

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000105

Gnomad OTH

AF:

0.00776

GnomAD2 exomes

AF:

0.00232

AC:

580

AN:

250414

AF XY:

0.00162

show subpopulations

Gnomad AFR exome

AF:

0.0323

Gnomad AMR exome

AF:

0.00125

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000354

Gnomad OTH exome

AF:

0.00115

GnomAD4 exome

AF:

0.000960

AC:

1402

AN:

1461094

Hom.:

Cov.:

AF XY:

0.000805

AC XY:

585

AN XY:

726846

show subpopulations

African (AFR)

AF:

0.0351

AC:

1172

AN:

33424

American (AMR)

AF:

0.00143

AC:

AN:

44646

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26098

East Asian (EAS)

AF:

0.00

AC:

AN:

39676

South Asian (SAS)

AF:

0.0000464

AC:

AN:

86224

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53394

Middle Eastern (MID)

AF:

0.00122

AC:

AN:

5760

European-Non Finnish (NFE)

AF:

0.0000207

AC:

AN:

1111516

Other (OTH)

AF:

0.00219

AC:

132

AN:

60356

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.450

Heterozygous variant carriers

153

229

306

382

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

108

144

180

<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:

0.00941

AC:

1415

AN:

150294

Hom.:

Cov.:

AF XY:

0.00926

AC XY:

681

AN XY:

73552

show subpopulations

African (AFR)

AF:

0.0320

AC:

1324

AN:

41326

American (AMR)

AF:

0.00443

AC:

AN:

15116

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3462

East Asian (EAS)

AF:

0.00

AC:

AN:

5122

South Asian (SAS)

AF:

0.000208

AC:

AN:

4798

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10432

Middle Eastern (MID)

AF:

0.00

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.000105

AC:

AN:

66756

Other (OTH)

AF:

0.00768

AC:

AN:

2084

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

136

204

272

340

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<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:

0.000173

Hom.:

Bravo

AF:

0.0106

ESP6500AA

AF:

0.0275

AC:

121

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.00268

AC:

325

Asia WGS

AF:

0.00115

AC:

AN:

3478

ClinVar

ClinVar submissions

Significance:Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.66

BayesDel_noAF

Benign

-0.70

CADD

Benign

6.3

(source)

DANN

Benign

0.85

DEOGEN2

Benign

0.030

Eigen

Benign

-0.71

Eigen_PC

Benign

-0.86

FATHMM_MKL

Benign

0.034

LIST_S2

Benign

0.79

MetaRNN

Benign

0.0046

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.69

PhyloP100

-0.045

PrimateAI

Benign

0.24

PROVEAN

Benign

-0.46

REVEL

Benign

0.062

Sift

Benign

0.16

Sift4G

Benign

0.16

Polyphen

0.95

Vest4

0.30

MVP

0.048

MPC

0.038

ClinPred

0.0089

GERP RS

0.86

Varity_R

0.031

gMVP

0.13

Mutation Taster

=99/1

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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