Genetic Variant NM_001382683.1:c.1051A>C (chr13-97391324-A-C) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_ModerateBP6_Moderate

The NM_001382683.1(MBNL2):c.1051A>C(p.Asn351His) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000332 in 1,205,370 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000033 ( 0 hom. )

Consequence

MBNL2
NM_001382683.1 missense, splice_region

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: 2.36

Variant links:

Genes affected

MBNL2 (HGNC:16746): (muscleblind like splicing regulator 2) This gene is a member of the muscleblind protein family which was initially described in Drosophila melanogaster. This gene encodes a C3H-type zinc finger protein that modulates alternative splicing of pre-mRNAs. Muscleblind proteins bind specifically to expanded dsCUG RNA but not to normal size CUG repeats and may thereby play a role in the pathophysiology of myotonic dystrophy. Several alternatively spliced transcript variants have been described but the full-length natures of only some have been determined. [provided by RefSeq, Mar 2012]

MBNL2 links:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.20134649).

BP6

Variant 13-97391324-A-C is Benign according to our data. Variant chr13-97391324-A-C is described in ClinVar as [Likely_benign]. Clinvar id is 3543869.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MBNL2	NM_001382683.1 link	c.1051A>C	p.Asn351His	missense_variant, splice_region_variant	Exon 9 of 9	ENST00000679496.1	NP_001369612.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MBNL2	ENST00000679496.1 link	c.1051A>C	p.Asn351His	missense_variant, splice_region_variant	Exon 9 of 9		NM_001382683.1	ENSP00000505596.1		A0A7P0T9I3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000404

AC:

AN:

247468

Hom.:

AF XY:

0.00

AC XY:

AN XY:

133894

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:

0.00000894

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000332

AC:

AN:

1205370

Hom.:

Cov.:

AF XY:

0.00000327

AC XY:

AN XY:

611948

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

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:

0.00000455

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000469

Hom.:

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Benign:1

Sep 04, 2024

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

0.055

BayesDel_addAF

Benign

-0.070

BayesDel_noAF

Benign

-0.34

CADD

Benign

DANN

Benign

0.97

DEOGEN2

Benign

0.083

.;T;.

Eigen

Uncertain

0.42

Eigen_PC

Uncertain

0.38

FATHMM_MKL

Uncertain

0.81

LIST_S2

Benign

0.58

T;T;.

M_CAP

Benign

0.011

MetaRNN

Benign

0.20

T;T;T

MetaSVM

Benign

-0.97

MutationAssessor

Benign

0.46

.;N;.

PROVEAN

Benign

-0.74

N;N;N

REVEL

Benign

0.062

Sift

Benign

0.39

T;T;T

Sift4G

Benign

0.58

T;T;T

Polyphen

0.0

.;B;.

Vest4

0.24

MutPred

0.27

.;Gain of catalytic residue at E335 (P = 0.0102);.;

MVP

0.86

ClinPred

0.22

GERP RS

4.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.034

gMVP

0.14

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

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