2-148161266-A-G

Position:

• chr2-148161266-A-G

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001378120.1(MBD5):​c.-924-17434A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0876 in 152,234 control chromosomes in the GnomAD database, including 648 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.088 (648 hom., cov: 32)
• Consequence: MBD5 NM_001378120.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.47

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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.78).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.134 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MBD5	NM_001378120.1	c.-924-17434A>G		intron_variant		ENST00000642680.2	NP_001365049.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MBD5	ENST00000642680.2	c.-924-17434A>G		intron_variant			NM_001378120.1	ENSP00000493871

Frequencies

GnomAD3 genomes AF: 0.0876 AC: 13329 AN: 152116 Hom.: 646 Cov.: 32

Gnomad AFR AF: 0.0426

Gnomad AMI AF: 0.0987

Gnomad AMR AF: 0.0862

Gnomad ASJ AF: 0.178

Gnomad EAS AF: 0.102

Gnomad SAS AF: 0.142

Gnomad FIN AF: 0.0659

Gnomad MID AF: 0.120

Gnomad NFE AF: 0.108

Gnomad OTH AF: 0.108

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.0876 AC: 13334 AN: 152234 Hom.: 648 Cov.: 32 AF XY: 0.0869 AC XY: 6465 AN XY: 74422

Gnomad4 AFR AF: 0.0427

Gnomad4 AMR AF: 0.0860

Gnomad4 ASJ AF: 0.178

Gnomad4 EAS AF: 0.102

Gnomad4 SAS AF: 0.142

Gnomad4 FIN AF: 0.0659

Gnomad4 NFE AF: 0.108

Gnomad4 OTH AF: 0.107

Alfa AF: 0.0932 Hom.: 365

Bravo AF: 0.0864

Asia WGS AF: 0.119 AC: 413 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	11
DANN	Benign	0.85

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: rs10497031; hg19: chr2-148918835;