2-148469532-G-C

Variant names:

• chr2-148469532-G-C
• rs558138423
• NM_001378120.1:c.1589G>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001378120.1(MBD5):​c.1589G>C​(p.Ser530Thr) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S530N) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: MBD5 NM_001378120.1 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.54
• Publications: 0 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.14262664).

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.1589G>C	p.Ser530Thr	missense	Exon 8 of 14	NP_001365049.1
	MBD5	NM_001438854.1		c.1589G>C	p.Ser530Thr	missense	Exon 9 of 15	NP_001425783.1
	MBD5	NM_001438856.1		c.1589G>C	p.Ser530Thr	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.1589G>C	p.Ser530Thr	missense	Exon 8 of 14	ENSP00000493871.2
	MBD5	ENST00000407073.5	TSL:1	c.1589G>C	p.Ser530Thr	missense	Exon 9 of 15	ENSP00000386049.1
	MBD5	ENST00000638043.2	TSL:5	c.1589G>C	p.Ser530Thr	missense	Exon 8 of 14	ENSP00000490728.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.10	T
BayesDel_noAF	Benign	-0.38
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.041	T
Eigen	Benign	0.026
Eigen_PC	Benign	0.12
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.81	T
M_CAP	Benign	0.0096	T
MetaRNN	Benign	0.14	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	0.90	L
PhyloP100		4.5
PrimateAI	Uncertain	0.70	T
PROVEAN	Benign	-0.91	N
REVEL	Benign	0.067
Sift	Uncertain	0.0040	D
Sift4G	Benign	0.28	T
Polyphen		0.40	B
Vest4		0.55
MutPred		0.14		Loss of sheet (P = 0.0817)
MVP		0.28
MPC		0.25
ClinPred		0.67	D
GERP RS		4.2
Varity_R		0.13
gMVP		0.25
Mutation Taster		=93/7	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: rs558138423; hg19: chr2-149227101;