rs114314967

chr2-148469973-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001378120.1(MBD5):c.2030G>A(p.Ser677Asn) variant causes a missense change. The variant allele was found at a frequency of 0.00237 in 1,613,950 control chromosomes in the GnomAD database, including 11 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0020 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0024 (10 hom.)
• Consequence: MBD5 NM_001378120.1 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: 6.80

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0047388375).
• BP6: Variant 2-148469973-G-A is Benign according to our data. Variant chr2-148469973-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 95899.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-148469973-G-A is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00201 (306/152300) while in subpopulation AMR AF= 0.00347 (53/15294). AF 95% confidence interval is 0.00272. There are 1 homozygotes in gnomad4. There are 149 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High AC in GnomAd at 305 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MBD5	NM_001378120.1	c.2030G>A	p.Ser677Asn	missense_variant	8/14	ENST00000642680.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MBD5	ENST00000642680.2	c.2030G>A	p.Ser677Asn	missense_variant	8/14		NM_001378120.1

Frequencies

GnomAD3 genomes AF: 0.00200 AC: 305 AN: 152182 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00347

Gnomad ASJ AF: 0.00576

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00145

Gnomad FIN AF: 0.000283

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.00281

Gnomad OTH AF: 0.00335

GnomAD3 exomes AF: 0.00229 AC: 574 AN: 250672 Hom.: 0 AF XY: 0.00249 AC XY: 337 AN XY: 135438

Gnomad AFR exome AF: 0.000554

Gnomad AMR exome AF: 0.00151

Gnomad ASJ exome AF: 0.00657

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00170

Gnomad FIN exome AF: 0.0000463

Gnomad NFE exome AF: 0.00331

Gnomad OTH exome AF: 0.00311

GnomAD4 exome AF: 0.00240 AC: 3511 AN: 1461650 Hom.: 10 Cov.: 33 AF XY: 0.00253 AC XY: 1840 AN XY: 727128

Gnomad4 AFR exome AF: 0.00111

Gnomad4 AMR exome AF: 0.00197

Gnomad4 ASJ exome AF: 0.00681

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00202

Gnomad4 FIN exome AF: 0.000150

Gnomad4 NFE exome AF: 0.00246

Gnomad4 OTH exome AF: 0.00384

GnomAD4 genome AF: 0.00201 AC: 306 AN: 152300 Hom.: 1 Cov.: 32 AF XY: 0.00200 AC XY: 149 AN XY: 74466

Gnomad4 AFR AF: 0.000505

Gnomad4 AMR AF: 0.00347

Gnomad4 ASJ AF: 0.00576

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00145

Gnomad4 FIN AF: 0.000283

Gnomad4 NFE AF: 0.00281

Gnomad4 OTH AF: 0.00331

Alfa AF: 0.00301 Hom.: 4

Bravo AF: 0.00242

TwinsUK AF: 0.00135 AC: 5

ALSPAC AF: 0.00208 AC: 8

ESP6500AA AF: 0.000681 AC: 3

ESP6500EA AF: 0.00256 AC: 22

ExAC AF: 0.00246 AC: 299

Asia WGS AF: 0.00289 AC: 10 AN: 3478

EpiCase AF: 0.00376

EpiControl AF: 0.00551

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	May 11, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 07, 2015	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 17, 2014	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. -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Jul 17, 2018	- -

not provided Benign:3

Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Dec 01, 2023	MBD5: BS1 -

Intellectual disability, autosomal dominant 1 Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Mar 28, 2022	- -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -

Inborn genetic diseases Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 30, 2017

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. -

MBD5-related condition Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 05, 2021

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.085
BayesDel_addAF	Benign	-0.57	T
BayesDel_noAF	Benign	-0.59
Cadd	Benign	21
Dann	Uncertain	0.99
DEOGEN2	Benign	0.024	T;.;.;.;T
Eigen	Benign	0.14
Eigen_PC	Uncertain	0.25
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.73	T;.;T;T;T
M_CAP	Benign	0.0041	T
MetaRNN	Benign	0.0047	T;T;T;T;T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	0.60	N;.;.;N;.
MutationTaster	Benign	0.62	D;D
PrimateAI	Uncertain	0.57	T
PROVEAN	Benign	0.070	N;.;.;.;N
REVEL	Benign	0.12
Sift	Benign	0.15	T;.;.;.;T
Sift4G	Benign	0.17	T;.;.;T;T
Polyphen		0.0	B;.;.;B;.
Vest4		0.31
MVP		0.19
MPC		0.29
ClinPred		0.027	T
GERP RS		4.0
Varity_R		0.13
gMVP		0.21

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

Other links and lift over

dbSNP: rs114314967; hg19: chr2-149227542;