chr2-148458195-T-C

Position:

chr2-148458195-T-C

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 0P and 18B. BP4_ModerateBP6_Very_StrongBS1BS2

The NM_001378120.1(MBD5):c.-556-8T>C variant causes a splice region, 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, intron

Scores

Splicing: ADA: 0.006506

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 2.87

Variant links:

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]

MBD5 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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 GnomAd4 at 522 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MBD5	NM_001378120.1 link	c.-556-8T>C		splice_region_variant, intron_variant		ENST00000642680.2	NP_001365049.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MBD5	ENST00000642680.2 link	c.-556-8T>C		splice_region_variant, intron_variant			NM_001378120.1	ENSP00000493871.2		A0A2R8YDL9

Frequencies

GnomAD3 genomes

AF:

0.00343

AC:

522

AN:

152212

Hom.:

Cov.:

show subpopulations

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.:

Cov.:

AF XY:

0.00360

AC XY:

453

AN XY:

125678

show subpopulations

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.:

Cov.:

AF XY:

0.00333

AC XY:

248

AN XY:

74484

show subpopulations

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.:

Bravo

AF:

0.00351

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

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

Aug 01, 2024

MBD5: BS1, BS2 -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.35

CADD

Benign

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

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