chr2-148469054-C-G

Variant names:

• chr2-148469054-C-G
• rs536900412
• NM_001378120.1:c.1111C>G

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_001378120.1(MBD5):​c.1111C>G​(p.Gln371Glu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000727 in 1,613,950 control chromosomes in the GnomAD database, including 18 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00045 (4 hom., cov: 32)
  • Exomes 𝑓: 0.00076 (14 hom.)
• Consequence: MBD5 NM_001378120.1 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:6
• Conservation: PhyloP100: 7.62
• Publications: 1 publications found

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 Gene-Disease associations (from GenCC):

• complex neurodevelopmental disorder

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• intellectual disability, autosomal dominant 1

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
• autosomal dominant non-syndromic intellectual disability

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.006460339).
• BP6: Variant 2-148469054-C-G is Benign according to our data. Variant chr2-148469054-C-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 206068.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.000447 (68/152166) while in subpopulation SAS AF = 0.0141 (68/4826). AF 95% confidence interval is 0.0114. There are 4 homozygotes in GnomAd4. There are 58 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 68 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001378120.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MBD5	NM_001378120.1	MANE Select	c.1111C>G	p.Gln371Glu	missense	Exon 8 of 14	NP_001365049.1
	MBD5	NM_001438854.1		c.1111C>G	p.Gln371Glu	missense	Exon 9 of 15	NP_001425783.1
	MBD5	NM_001438856.1		c.1111C>G	p.Gln371Glu	missense	Exon 9 of 15	NP_001425785.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MBD5	ENST00000642680.2	MANE Select	c.1111C>G	p.Gln371Glu	missense	Exon 8 of 14	ENSP00000493871.2
	MBD5	ENST00000407073.5	TSL:1	c.1111C>G	p.Gln371Glu	missense	Exon 9 of 15	ENSP00000386049.1
	MBD5	ENST00000638043.2	TSL:5	c.1111C>G	p.Gln371Glu	missense	Exon 8 of 14	ENSP00000490728.2

Frequencies

GnomAD3 genomes AF: 0.000447 AC: 68 AN: 152048 Hom.: 4 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0141

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00156 AC: 392 AN: 251040 AF XY: 0.00210

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000882

Gnomad OTH exome AF: 0.000653

GnomAD4 exome AF: 0.000757 AC: 1106 AN: 1461784 Hom.: 14 Cov.: 33 AF XY: 0.00107 AC XY: 779 AN XY: 727194

African (AFR) AF: 0.0000299 AC: 1 AN: 33474

American (AMR) AF: 0.0000224 AC: 1 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26128

East Asian (EAS) AF: 0.00 AC: 0 AN: 39694

South Asian (SAS) AF: 0.0122 AC: 1051 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5766

European-Non Finnish (NFE) AF: 0.00000540 AC: 6 AN: 1111938

Other (OTH) AF: 0.000762 AC: 46 AN: 60388

GnomAD4 genome AF: 0.000447 AC: 68 AN: 152166 Hom.: 4 Cov.: 32 AF XY: 0.000780 AC XY: 58 AN XY: 74370

African (AFR) AF: 0.00 AC: 0 AN: 41510

American (AMR) AF: 0.00 AC: 0 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5164

South Asian (SAS) AF: 0.0141 AC: 68 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10594

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68012

Other (OTH) AF: 0.00 AC: 0 AN: 2108

Alfa AF: 0.000128 Hom.: 0

Bravo AF: 0.0000756

ExAC AF: 0.00182 AC: 221

Asia WGS AF: 0.00433 AC: 15 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	2	not specified (2)
-	-	1	Inborn genetic diseases (1)
-	-	1	Intellectual disability, autosomal dominant 1 (1)
-	1	-	Intellectual Disability, Dominant (1)
-	-	1	MBD5-related disorder (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.37	T
BayesDel_noAF	Benign	-0.30
CADD	Uncertain	23
DANN	Uncertain	0.98
DEOGEN2	Benign	0.081	T
Eigen	Uncertain	0.61
Eigen_PC	Pathogenic	0.67
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.90	D
MetaRNN	Benign	0.0065	T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	0.97	L
PhyloP100		7.6
PrimateAI	Uncertain	0.62	T
PROVEAN	Benign	-1.2	N
REVEL	Benign	0.23
Sift	Pathogenic	0.0	D
Sift4G	Benign	0.20	T
Polyphen		0.97	D
Vest4		0.55
MutPred		0.076		Loss of sheet (P = 0.1501)
MVP		0.28
MPC		0.20
ClinPred		0.17	T
GERP RS		5.5
PromoterAI		-0.013	Neutral
Varity_R		0.47
gMVP		0.32
Mutation Taster		=95/5	polymorphism

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

Other links and lift over

dbSNP: rs536900412; hg19: chr2-149226623;