rs61751447

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 2P and 7B. PM2BP4_StrongBP6_ModerateBP7

The NM_001110792.2(MECP2):​c.984C>T​(p.Val328Val) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★). Synonymous variant affecting the same amino acid position (i.e. V328V) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 23)
Exomes 𝑓: 0.0000018 ( 0 hom. 2 hem. )
Failed GnomAD Quality Control

Consequence

MECP2
NM_001110792.2 synonymous

Scores

5

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: 0.0190

Publications

1 publications found
Variant links:
Genes affected
MECP2 (HGNC:6990): (methyl-CpG binding protein 2) DNA methylation is the major modification of eukaryotic genomes and plays an essential role in mammalian development. Human proteins MECP2, MBD1, MBD2, MBD3, and MBD4 comprise a family of nuclear proteins related by the presence in each of a methyl-CpG binding domain (MBD). Each of these proteins, with the exception of MBD3, is capable of binding specifically to methylated DNA. MECP2, MBD1 and MBD2 can also repress transcription from methylated gene promoters. In contrast to other MBD family members, MECP2 is X-linked and subject to X inactivation. MECP2 is dispensible in stem cells, but is essential for embryonic development. MECP2 gene mutations are the cause of most cases of Rett syndrome, a progressive neurologic developmental disorder and one of the most common causes of cognitive disability in females. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Oct 2015]
MECP2 Gene-Disease associations (from GenCC):
  • chromosome Xq28 duplication syndrome
    Inheritance: XL Classification: DEFINITIVE Submitted by: G2P
  • Rett syndrome
    Inheritance: XL Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), Ambry Genetics, ClinGen, G2P
  • severe neonatal-onset encephalopathy with microcephaly
    Inheritance: XL Classification: DEFINITIVE, SUPPORTIVE Submitted by: G2P, Orphanet
  • syndromic X-linked intellectual disability Lubs type
    Inheritance: XL Classification: DEFINITIVE Submitted by: G2P
  • atypical Rett syndrome
    Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
  • non-syndromic X-linked intellectual disability
    Inheritance: XL Classification: SUPPORTIVE Submitted by: Orphanet
  • X-linked intellectual disability-psychosis-macroorchidism syndrome
    Inheritance: XL Classification: SUPPORTIVE Submitted by: Orphanet
  • systemic lupus erythematosus
    Inheritance: Unknown Classification: SUPPORTIVE Submitted by: Orphanet

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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 (BayesDel_addAF=-0.32196).
BP6
Variant X-154030880-G-A is Benign according to our data. Variant chrX-154030880-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 1565354.Status of the report is criteria_provided_single_submitter, 1 stars.
BP7
Synonymous conserved (PhyloP=0.019 with no splicing effect.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
MECP2NM_001110792.2 linkc.984C>T p.Val328Val synonymous_variant Exon 3 of 3 ENST00000453960.7 NP_001104262.1 P51608-2A0A140VKC4Q59FJ6
MECP2NM_004992.4 linkc.948C>T p.Val316Val synonymous_variant Exon 4 of 4 ENST00000303391.11 NP_004983.1 P51608-1D3YJ43Q59FJ6

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
MECP2ENST00000453960.7 linkc.984C>T p.Val328Val synonymous_variant Exon 3 of 3 1 NM_001110792.2 ENSP00000395535.2 P51608-2
MECP2ENST00000303391.11 linkc.948C>T p.Val316Val synonymous_variant Exon 4 of 4 1 NM_004992.4 ENSP00000301948.6 P51608-1

Frequencies

GnomAD3 genomes
Cov.:
23
GnomAD2 exomes
AF:
0.00000545
AC:
1
AN:
183500
AF XY:
0.0000147
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
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
Data not reliable, filtered out with message: AS_VQSR
AF:
0.00000182
AC:
2
AN:
1098248
Hom.:
0
Cov.:
35
AF XY:
0.00000550
AC XY:
2
AN XY:
363604
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
26403
American (AMR)
AF:
0.00
AC:
0
AN:
35207
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
19386
East Asian (EAS)
AF:
0.00
AC:
0
AN:
30206
South Asian (SAS)
AF:
0.0000185
AC:
1
AN:
54144
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
40531
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
4137
European-Non Finnish (NFE)
AF:
0.00000119
AC:
1
AN:
842136
Other (OTH)
AF:
0.00
AC:
0
AN:
46098
GnomAD4 genome
Cov.:
23
ExAC
AF:
0.0000165
AC:
2

ClinVar

Significance: Likely benign
Submissions summary: Benign:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Severe neonatal-onset encephalopathy with microcephaly Benign:1
Jun 16, 2021
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Benign
-0.32
T
BayesDel_noAF
Benign
-0.55
CADD
Benign
5.9
DANN
Benign
0.72
FATHMM_MKL
Benign
0.38
N
PhyloP100
0.019
Vest4
0.68
GERP RS
1.0
Mutation Taster
=100/0
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

Publications

Other links and lift over

dbSNP: rs61751447; hg19: chrX-153296331; API