Genetic Variant MUCL1:p.Pro74Leu (chr12-54856890-C-T) – ACMG Classification: Likely_benign (-4 pts)

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM2BP4_StrongBP6_Moderate

The NM_058173.3(MUCL1):c.221C>T(p.Pro74Leu) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000219 in 1,461,452 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 0.000022 ( 0 hom. )

Consequence

MUCL1
NM_058173.3 missense, splice_region

Scores

Splicing: ADA: 0.01173

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: -2.18

Variant links:

Genes affected

MUCL1 (HGNC:30588): (mucin like 1) Predicted to be located in Golgi lumen and plasma membrane. [provided by Alliance of Genome Resources, Apr 2022]

MUCL1 links:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.059789866).

BP6

Variant 12-54856890-C-T is Benign according to our data. Variant chr12-54856890-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 3875875.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MUCL1	NM_058173.3 link	c.221C>T	p.Pro74Leu	missense_variant, splice_region_variant	Exon 3 of 4	ENST00000308796.11	NP_477521.1	Q96DR8
MUCL1	XM_047428272.1 link	c.221C>T	p.Pro74Leu	missense_variant, splice_region_variant	Exon 4 of 5		XP_047284228.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
MUCL1	ENST00000308796.11 link	c.221C>T	p.Pro74Leu	missense_variant, splice_region_variant	Exon 3 of 4	1	NM_058173.3	ENSP00000311364.5	Q96DR8
MUCL1	ENST00000546809.5 link	c.206C>T	p.Pro69Leu	missense_variant, splice_region_variant	Exon 3 of 4	3		ENSP00000449369.1	F8VV13
MUCL1	ENST00000547990.1 link	n.520C>T		splice_region_variant, non_coding_transcript_exon_variant	Exon 3 of 4	4
MUCL1	ENST00000652289.1 link	n.521C>T		splice_region_variant, non_coding_transcript_exon_variant	Exon 3 of 5

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000403

AC:

AN:

248328

Hom.:

AF XY:

0.00

AC XY:

AN XY:

134386

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:

0.00000902

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000219

AC:

AN:

1461452

Hom.:

Cov.:

AF XY:

0.0000193

AC XY:

AN XY:

727004

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000224

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:

0.0000166

GnomAD4 genome

Cov.:

EpiCase

AF:

0.0000546

EpiControl

AF:

0.0000594

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Benign:1

Jan 18, 2025

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.28

BayesDel_noAF

Benign

-0.63

CADD

Benign

4.4

DANN

Benign

0.38

DEOGEN2

Benign

0.026

T;T;T

Eigen

Benign

-1.4

Eigen_PC

Benign

-1.7

FATHMM_MKL

Benign

0.0013

LIST_S2

Benign

0.41

T;T;T

M_CAP

Benign

0.00052

MetaRNN

Benign

0.060

T;T;T

MetaSVM

Benign

-1.0

PrimateAI

Benign

0.20

PROVEAN

Benign

2.2

N;N;.

REVEL

Benign

0.031

Sift

Benign

1.0

T;T;.

Sift4G

Uncertain

0.034

D;T;D

Polyphen

0.0

.;B;.

Vest4

0.058

MutPred

0.34

.;Gain of catalytic residue at P74 (P = 0.004);.;

MVP

0.11

MPC

0.0030

ClinPred

0.035

GERP RS

-5.8

Varity_R

0.018

gMVP

0.030

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.012

dbscSNV1_RF

Benign

0.41

SpliceAI score (max)

0.19

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