2-148458195-T-C

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BS1 BS2

The NM_001378120.1(MBD5):c.-556-8T>C variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0036 in 400,324 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts 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 Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0034 (3 hom., cov: 32)
  • Exomes 𝑓: 0.0037 (1 hom.)
• Consequence: MBD5 NM_001378120.1 splice_region, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.006506
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 2.87

Genes affected

MBD5 (HGNC:20444): (methyl-CpG binding domain protein 5) This gene encodes a member of the methyl-CpG-binding domain (MBD) family. The MBD consists of about 70 residues and is the minimal region required for a methyl-CpG-binding protein binding specifically to methylated DNA. In addition to the MBD domain, this protein contains a PWWP domain (Pro-Trp-Trp-Pro motif), which consists of 100-150 amino acids and is found in numerous proteins that are involved in cell division, growth and differentiation. Mutations in this gene cause an autosomal dominant type of cognitive disability. The encoded protein interacts with the polycomb repressive complex PR-DUB which catalyzes the deubiquitination of a lysine residue of histone 2A. Haploinsufficiency of this gene is associated with a syndrome involving microcephaly, intellectual disabilities, severe speech impairment, and seizures. Alternatively spliced transcript variants have been found, but their full-length nature is not determined. [provided by RefSeq, Jul 2017]

ACMG classification

Verdict is Benign. Variant got -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.35).
• BP6: Variant 2-148458195-T-C is Benign according to our data. Variant chr2-148458195-T-C is described in ClinVar as [Benign]. Clinvar id is 138171.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-148458195-T-C is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00343 (522/152330) while in subpopulation AMR AF= 0.00543 (83/15282). AF 95% confidence interval is 0.00487. There are 3 homozygotes in gnomad4. There are 248 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd at 522 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MBD5	NM_001378120.1	c.-556-8T>C		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000642680.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MBD5	ENST00000642680.2	c.-556-8T>C		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant			NM_001378120.1

Frequencies

GnomAD3 genomes AF: 0.00343 AC: 522 AN: 152212 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.000916

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00544

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00165

Gnomad FIN AF: 0.00188

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00532

Gnomad OTH AF: 0.00430

GnomAD4 exome AF: 0.00371 AC: 921 AN: 247994 Hom.: 1 Cov.: 0 AF XY: 0.00360 AC XY: 453 AN XY: 125678

Gnomad4 AFR exome AF: 0.000841

Gnomad4 AMR exome AF: 0.00415

Gnomad4 ASJ exome AF: 0.000543

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000311

Gnomad4 FIN exome AF: 0.00254

Gnomad4 NFE exome AF: 0.00471

Gnomad4 OTH exome AF: 0.00420

GnomAD4 genome AF: 0.00343 AC: 522 AN: 152330 Hom.: 3 Cov.: 32 AF XY: 0.00333 AC XY: 248 AN XY: 74484

Gnomad4 AFR AF: 0.000914

Gnomad4 AMR AF: 0.00543

Gnomad4 ASJ AF: 0.000576

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00166

Gnomad4 FIN AF: 0.00188

Gnomad4 NFE AF: 0.00532

Gnomad4 OTH AF: 0.00426

Alfa AF: 0.00445 Hom.: 0

Bravo AF: 0.00351

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Dec 05, 2013

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Feb 01, 2024

MBD5: BS1, BS2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.35
Cadd	Benign	15
Dann	Benign	0.92

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0065
dbscSNV1_RF	Benign	0.14
SpliceAI score (max)		0.16		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

Other links and lift over

dbSNP: rs140968376; hg19: chr2-149215764;