11-26561223-G-T

Position:

chr11-26561223-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001135091.2(MUC15):c.928C>A(p.Leu310Met) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000564 in 1,596,862 control chromosomes in the GnomAD database, with no homozygous occurrence. 1/1 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000048 ( 0 hom. )

Consequence

MUC15
NM_001135091.2 missense, splice_region

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.13

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 links:

ANO3 (HGNC:):

ANO3 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MUC15	NM_001135091.2 linkuse as main transcript	c.928C>A	p.Leu310Met	missense_variant, splice_region_variant	5/5	ENST00000529533.6	NP_001128563.1	Q8N387A0A0A0MT67
ANO3	NM_031418.4 linkuse as main transcript	c.1447+1444G>T		intron_variant		ENST00000256737.8	NP_113606.2	Q9BYT9-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MUC15	ENST00000529533.6 linkuse as main transcript	c.928C>A	p.Leu310Met	missense_variant, splice_region_variant	5/5	1	NM_001135091.2	ENSP00000431983.1		A0A0A0MT67
ANO3	ENST00000256737.8 linkuse as main transcript	c.1447+1444G>T		intron_variant		1	NM_031418.4	ENSP00000256737.3		Q9BYT9-1

Frequencies

GnomAD3 genomes

AF:

0.0000132

AC:

AN:

151874

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000132

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

GnomAD3 exomes

AF:

0.00000425

AC:

AN:

235104

Hom.:

AF XY:

0.00

AC XY:

AN XY:

127576

show subpopulations

Gnomad AFR exome

AF:

0.00

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:

0.00000928

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000484

AC:

AN:

1444988

Hom.:

Cov.:

AF XY:

0.00000278

AC XY:

AN XY:

718322

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000239

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:

0.00

Gnomad4 OTH exome

AF:

0.000100

GnomAD4 genome

AF:

0.0000132

AC:

AN:

151874

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74172

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.000132

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000151

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 10, 2024

The c.928C>A (p.L310M) alteration is located in exon 5 (coding exon 4) of the MUC15 gene. This alteration results from a C to A substitution at nucleotide position 928, causing the leucine (L) at amino acid position 310 to be replaced by a methionine (M). 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

Pathogenic

0.64

BayesDel_addAF

Benign

-0.045

BayesDel_noAF

Benign

-0.30

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.075

T;T;T;T;T

Eigen

Uncertain

0.36

Eigen_PC

Uncertain

0.34

FATHMM_MKL

Uncertain

0.85

LIST_S2

Benign

0.67

T;T;T;.;.

M_CAP

Benign

0.048

MetaRNN

Uncertain

0.44

T;T;T;T;T

MetaSVM

Benign

-0.76

MutationAssessor

Benign

1.1

.;.;L;.;.

PrimateAI

Benign

0.47

PROVEAN

Benign

-1.8

N;N;N;N;N

REVEL

Benign

0.28

Sift

Uncertain

0.010

D;D;D;D;D

Sift4G

Pathogenic

0.0

D;D;D;D;D

Polyphen

1.0

.;.;D;.;.

Vest4

0.53

MutPred

0.60

.;.;Loss of sheet (P = 0.0817);.;.;

MVP

0.16

MPC

0.17

ClinPred

0.96

GERP RS

4.5

Varity_R

0.19

gMVP

0.34

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.070

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