chr2-148342583-T-C

Position:

• chr2-148342583-T-C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_001378120.1(MBD5):​c.-557+247T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.275 in 151,708 control chromosomes in the GnomAD database, including 6,539 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.27 (6539 hom., cov: 31)
• Consequence: MBD5 NM_001378120.1 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.45

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 2-148342583-T-C is Benign according to our data. Variant chr2-148342583-T-C is described in ClinVar as [Benign]. Clinvar id is 1295206.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.359 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MBD5	NM_001378120.1	c.-557+247T>C		intron_variant		ENST00000642680.2	NP_001365049.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MBD5	ENST00000642680.2	c.-557+247T>C		intron_variant			NM_001378120.1	ENSP00000493871

Frequencies

GnomAD3 genomes AF: 0.275 AC: 41671 AN: 151590 Hom.: 6528 Cov.: 31

Gnomad AFR AF: 0.114

Gnomad AMI AF: 0.368

Gnomad AMR AF: 0.367

Gnomad ASJ AF: 0.303

Gnomad EAS AF: 0.252

Gnomad SAS AF: 0.350

Gnomad FIN AF: 0.311

Gnomad MID AF: 0.269

Gnomad NFE AF: 0.341

Gnomad OTH AF: 0.276

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

GnomAD4 genome AF: 0.275 AC: 41701 AN: 151708 Hom.: 6539 Cov.: 31 AF XY: 0.276 AC XY: 20429 AN XY: 74120

Gnomad4 AFR AF: 0.114

Gnomad4 AMR AF: 0.367

Gnomad4 ASJ AF: 0.303

Gnomad4 EAS AF: 0.253

Gnomad4 SAS AF: 0.351

Gnomad4 FIN AF: 0.311

Gnomad4 NFE AF: 0.341

Gnomad4 OTH AF: 0.280

Alfa AF: 0.320 Hom.: 1073

Bravo AF: 0.270

Asia WGS AF: 0.335 AC: 1161 AN: 3466

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 23, 2018

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	11
DANN	Benign	0.83

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: rs2602352; hg19: chr2-149100152;