2-148469930-C-T

Variant names:

• chr2-148469930-C-T
• rs1057520996
• NM_001378120.1:c.1987C>T
• MBD5 p.Pro663Ser

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 2P and 7B. PM2 BP4_Moderate BP6 BS1

The NM_001378120.1(MBD5):​c.1987C>T​(p.Pro663Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,461,684 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P663T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: MBD5 NM_001378120.1 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:1
• Conservation: PhyloP100: 3.45
• 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: Likely_benign. The variant received -5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.07971865).
• BP6: Variant 2-148469930-C-T is Benign according to our data. Variant chr2-148469930-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 381255.
• BS1: Variant frequency is greater than expected in population amr. GnomAdExome4 allele frequency = 0.00000274 (4/1461684) while in subpopulation AMR AF = 0.0000671 (3/44704). AF 95% confidence interval is 0.0000178. There are 0 homozygotes in GnomAdExome4. There are 0 alleles in the male GnomAdExome4 subpopulation. Median coverage is 33. This position passed quality control check.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MBD5	NM_001378120.1	MANE Select	c.1987C>T	p.Pro663Ser	missense	Exon 8 of 14	NP_001365049.1	A0A2R8YDL9
	MBD5	NM_001438854.1		c.1987C>T	p.Pro663Ser	missense	Exon 9 of 15	NP_001425783.1
	MBD5	NM_001438856.1		c.1987C>T	p.Pro663Ser	missense	Exon 9 of 15	NP_001425785.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MBD5	ENST00000642680.2	MANE Select	c.1987C>T	p.Pro663Ser	missense	Exon 8 of 14	ENSP00000493871.2	A0A2R8YDL9
	MBD5	ENST00000407073.5	TSL:1	c.1987C>T	p.Pro663Ser	missense	Exon 9 of 15	ENSP00000386049.1	Q9P267-1
	MBD5	ENST00000638043.2	TSL:5	c.1987C>T	p.Pro663Ser	missense	Exon 8 of 14	ENSP00000490728.2	A0A1B0GW10

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000160 AC: 4 AN: 250622 AF XY: 0.00000738

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000116

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461684 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 727160

African (AFR) AF: 0.0000299 AC: 1 AN: 33458

American (AMR) AF: 0.0000671 AC: 3 AN: 44704

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26126

East Asian (EAS) AF: 0.00 AC: 0 AN: 39690

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53410

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111894

Other (OTH) AF: 0.00 AC: 0 AN: 60382

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	1	not specified (2)
-	1	-	Intellectual disability, autosomal dominant 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.068
BayesDel_addAF	Benign	-0.35	T
BayesDel_noAF	Benign	-0.51
CADD	Benign	18
DANN	Benign	0.87
DEOGEN2	Benign	0.030	T
Eigen	Benign	-0.18
Eigen_PC	Benign	0.039
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Uncertain	0.86	D
M_CAP	Benign	0.0040	T
MetaRNN	Benign	0.080	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-0.75	N
PhyloP100		3.5
PrimateAI	Benign	0.47	T
PROVEAN	Benign	-0.42	N
REVEL	Benign	0.020
Sift	Benign	0.20	T
Sift4G	Benign	1.0	T
Varity_R		0.060
gMVP		0.16
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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs1057520996; hg19: chr2-149227499;