rs62621673

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBS1BS2

The NM_001110792.2(MECP2):​c.*328G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00479 in 316,280 control chromosomes in the GnomAD database, including 3 homozygotes. There are 464 hemizygotes in GnomAD. 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 0.0047 ( 2 hom., 150 hem., cov: 23)
Exomes 𝑓: 0.0049 ( 1 hom. 314 hem. )

Consequence

MECP2
NM_001110792.2 3_prime_UTR

Scores

2

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 0.0790

Publications

0 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: Benign. The variant received -12 ACMG points.

BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.81).
BS1
Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00469 (519/110748) while in subpopulation NFE AF = 0.00655 (346/52815). AF 95% confidence interval is 0.00598. There are 2 homozygotes in GnomAd4. There are 150 alleles in the male GnomAd4 subpopulation. Median coverage is 23. This position passed quality control check.
BS2
High AC in GnomAd4 at 519 XL,Unknown,AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
MECP2NM_001110792.2 linkc.*328G>A 3_prime_UTR_variant Exon 3 of 3 ENST00000453960.7 NP_001104262.1 P51608-2A0A140VKC4Q59FJ6
MECP2NM_004992.4 linkc.*328G>A 3_prime_UTR_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.*328G>A 3_prime_UTR_variant Exon 3 of 3 1 NM_001110792.2 ENSP00000395535.2 P51608-2
MECP2ENST00000303391.11 linkc.*328G>A 3_prime_UTR_variant Exon 4 of 4 1 NM_004992.4 ENSP00000301948.6 P51608-1

Frequencies

GnomAD3 genomes
AF:
0.00469
AC:
519
AN:
110694
Hom.:
2
Cov.:
23
show subpopulations
Gnomad AFR
AF:
0.00228
Gnomad AMI
AF:
0.00293
Gnomad AMR
AF:
0.00201
Gnomad ASJ
AF:
0.00646
Gnomad EAS
AF:
0.000285
Gnomad SAS
AF:
0.00267
Gnomad FIN
AF:
0.00793
Gnomad MID
AF:
0.00420
Gnomad NFE
AF:
0.00655
Gnomad OTH
AF:
0.00533
GnomAD4 exome
AF:
0.00485
AC:
997
AN:
205532
Hom.:
1
Cov.:
0
AF XY:
0.00482
AC XY:
314
AN XY:
65154
show subpopulations
African (AFR)
AF:
0.00183
AC:
12
AN:
6541
American (AMR)
AF:
0.00202
AC:
21
AN:
10398
Ashkenazi Jewish (ASJ)
AF:
0.00527
AC:
30
AN:
5693
East Asian (EAS)
AF:
0.000542
AC:
6
AN:
11063
South Asian (SAS)
AF:
0.00135
AC:
33
AN:
24473
European-Finnish (FIN)
AF:
0.00891
AC:
92
AN:
10322
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
814
European-Non Finnish (NFE)
AF:
0.00612
AC:
761
AN:
124426
Other (OTH)
AF:
0.00356
AC:
42
AN:
11802
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.499
Heterozygous variant carriers
0
32
64
97
129
161
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Exome Hom
Variant carriers
0
10
20
30
40
50
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
GnomAD4 genome
AF:
0.00469
AC:
519
AN:
110748
Hom.:
2
Cov.:
23
AF XY:
0.00454
AC XY:
150
AN XY:
33008
show subpopulations
African (AFR)
AF:
0.00227
AC:
69
AN:
30391
American (AMR)
AF:
0.00201
AC:
21
AN:
10450
Ashkenazi Jewish (ASJ)
AF:
0.00646
AC:
17
AN:
2632
East Asian (EAS)
AF:
0.000286
AC:
1
AN:
3502
South Asian (SAS)
AF:
0.00268
AC:
7
AN:
2612
European-Finnish (FIN)
AF:
0.00793
AC:
47
AN:
5926
Middle Eastern (MID)
AF:
0.00461
AC:
1
AN:
217
European-Non Finnish (NFE)
AF:
0.00655
AC:
346
AN:
52815
Other (OTH)
AF:
0.00526
AC:
8
AN:
1520
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.506
Heterozygous variant carriers
0
19
38
58
77
96
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Genome Het
Genome Hom
Variant carriers
0
10
20
30
40
50
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
Alfa
AF:
0.00567
Hom.:
65
Bravo
AF:
0.00427

ClinVar

Significance: Benign
Submissions summary: Benign:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not specified Benign:1
Mar 10, 2010
RettBASE
Significance:Benign
Review Status:no assertion criteria provided
Collection Method:curation

- -

Rett syndrome Benign:1
Aug 14, 2023
Centre for Population Genomics, CPG
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:curation

This variant has been collected from RettBASE and curated to current modified ACMG/AMP criteria.Based on the classification scheme defined by the ClinGen Rett/Angelman-like Expert Panel for Rett/AS-like Disorders Specifications to the ACMG/AMP Variant Interpretation Guidelines VCEP 2.0, this variant is classified as benign. At least the following criteria are met: The allele frequency of this variant in at least one population in gnomAD is higher than the 0.03% threshold defined by the ClinGen Rett/Angelman-like Expert Panel for Rett/AS-like Disorders VCEP 2.0 (BA1). The variant is observed in at least 2 individuals with no features of Rett Syndrome (BS2). -

not provided Benign:1
-
Breakthrough Genomics, Breakthrough Genomics
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:not provided

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.81
CADD
Benign
0.83
DANN
Benign
0.88
PhyloP100
0.079
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: rs62621673; hg19: chrX-153295490; COSMIC: COSV100318122; COSMIC: COSV100318122; API