13-97343197-T-C

Variant summary

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

The NM_001382683.1(MBNL2):c.521T>C(p.Leu174Pro) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: MBNL2 NM_001382683.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.79

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]

ACMG classification

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	UniProt
MBNL2	NM_001382683.1	c.521T>C	p.Leu174Pro	missense_variant	4/9	ENST00000679496.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MBNL2	ENST00000679496.1	c.521T>C	p.Leu174Pro	missense_variant	4/9		NM_001382683.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 13, 2023

The c.521T>C (p.L174P) alteration is located in exon 4 (coding exon 3) of the MBNL2 gene. This alteration results from a T to C substitution at nucleotide position 521, causing the leucine (L) at amino acid position 174 to be replaced by a proline (P). 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	Benign	0.14
BayesDel_addAF	Pathogenic	0.21	D
BayesDel_noAF	Uncertain	0.060
Cadd	Uncertain	25
Dann	Uncertain	0.98
Eigen	Benign	0.088
Eigen_PC	Uncertain	0.27
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.84	T;T;.;T
M_CAP	Benign	0.030	D
MetaRNN	Uncertain	0.57	D;D;D;D
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	0.76	N;N;N;N
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Pathogenic	0.88	D
PROVEAN	Benign	-0.28	N;N;N;N
REVEL	Benign	0.23
Sift	Benign	0.43	T;T;T;T
Sift4G	Benign	0.16	T;T;T;T
Polyphen		0.066, 0.98	.;B;.;D
Vest4		0.86
MutPred		0.39		Loss of stability (P = 0.0028);Loss of stability (P = 0.0028);Loss of stability (P = 0.0028);Loss of stability (P = 0.0028);
MVP		0.63
MPC		1.4
ClinPred		0.52	D
GERP RS		5.7
Varity_R		0.42
gMVP		0.84

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr13-97995451; COSMIC: COSV59118635;