13-97334360-T-G

Variant names:

• chr13-97334360-T-G
• NM_001382683.1:c.259T>G

Variant summary

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

The NM_001382682.1(MBNL2):​c.-27T>G variant causes a 5 prime UTR premature start codon gain change. The variant allele was found at a frequency of 0.000000684 in 1,461,504 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: MBNL2 NM_001382682.1 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.99

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 rank	MANE	Protein	UniProt
MBNL2	NM_001382683.1	c.259T>G	p.Leu87Val	missense_variant	Exon 3 of 9	ENST00000679496.1	NP_001369612.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MBNL2	ENST00000679496.1	c.259T>G	p.Leu87Val	missense_variant	Exon 3 of 9		NM_001382683.1	ENSP00000505596.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461504 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727052

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: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jun 24, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.259T>G (p.L87V) alteration is located in exon 3 (coding exon 2) of the MBNL2 gene. This alteration results from a T to G substitution at nucleotide position 259, causing the leucine (L) at amino acid position 87 to be replaced by a valine (V). 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	0.88
BayesDel_addAF	Pathogenic	0.21	D
BayesDel_noAF	Uncertain	0.060
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.51	.;D;.;.
Eigen	Uncertain	0.53
Eigen_PC	Uncertain	0.57
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Pathogenic	0.99	D;D;.;D
M_CAP	Benign	0.052	D
MetaRNN	Uncertain	0.70	D;D;D;D
MetaSVM	Uncertain	-0.051	T
MutationAssessor	Benign	2.0	M;M;M;M
PrimateAI	Pathogenic	0.80	D
PROVEAN	Uncertain	-2.4	N;N;N;N
REVEL	Uncertain	0.53
Sift	Uncertain	0.0030	D;D;D;D
Sift4G	Uncertain	0.0030	D;D;D;D
Polyphen		0.47, 0.76	.;P;.;P
Vest4		0.68
MutPred		0.51		Gain of catalytic residue at R84 (P = 0.016);Gain of catalytic residue at R84 (P = 0.016);Gain of catalytic residue at R84 (P = 0.016);Gain of catalytic residue at R84 (P = 0.016);
MVP		0.61
MPC		2.0
ClinPred		0.90	D
GERP RS		5.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.34
gMVP		0.67

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: chr13-97986614;