2-148342440-G-A

Position:

• chr2-148342440-G-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_001378120.1(MBD5):​c.-557+104G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00529 in 152,032 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0053 (7 hom., cov: 32)
  • Failed GnomAD Quality Control
• Consequence: MBD5 NM_001378120.1 intron
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.782

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=-0.93).
• BP6: Variant 2-148342440-G-A is Benign according to our data. Variant chr2-148342440-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 1700716.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00529 (804/152032) while in subpopulation AFR AF= 0.0164 (681/41504). AF 95% confidence interval is 0.0154. There are 7 homozygotes in gnomad4. There are 367 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 804 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MBD5	NM_001378120.1	c.-557+104G>A		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+104G>A		intron_variant			NM_001378120.1	ENSP00000493871

Frequencies

GnomAD3 genomes AF: 0.00529 AC: 803 AN: 151914 Hom.: 7 Cov.: 32

Gnomad AFR AF: 0.0164

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00250

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000660

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000986

Gnomad OTH AF: 0.00526

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

GnomAD4 genome AF: 0.00529 AC: 804 AN: 152032 Hom.: 7 Cov.: 32 AF XY: 0.00494 AC XY: 367 AN XY: 74316

Gnomad4 AFR AF: 0.0164

Gnomad4 AMR AF: 0.00250

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000660

Gnomad4 NFE AF: 0.000986

Gnomad4 OTH AF: 0.00521

Alfa AF: 0.00499 Hom.: 3

Bravo AF: 0.00635

Asia WGS AF: 0.00202 AC: 8 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Feb 08, 2022

See Variant Classification Assertion Criteria. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	5.1
DANN	Benign	0.59

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: rs79508062; hg19: chr2-149100009;