NM_001110792.2:c.*8503delC

Variant names:

• chrX-154021863-TG-T
• rs267608360
• NM_001110792.2:c.*8503delC

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP6_Moderate BA1

The NM_001110792.2(MECP2):​c.*8503delC variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.040 (69 hom., 730 hem., cov: 16)
  • Exomes 𝑓: 0.040 (0 hom. 0 hem.)
  • Failed GnomAD Quality Control
• Consequence: MECP2 NM_001110792.2 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:2
• Conservation: PhyloP100: 1.18
• Publications: 0 publications found

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

ACMG classification

Our verdict: Benign. The variant received -10 ACMG points.

• BP6: Variant X-154021863-TG-T is Benign according to our data. Variant chrX-154021863-TG-T is described in ClinVar as [Benign]. Clinvar id is 143288.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0995 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MECP2	NM_001110792.2	c.*8503delC		3_prime_UTR_variant	Exon 3 of 3	ENST00000453960.7	NP_001104262.1
MECP2	NM_004992.4	c.*8503delC		3_prime_UTR_variant	Exon 4 of 4	ENST00000303391.11	NP_004983.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MECP2	ENST00000453960.7	c.*8503delC		3_prime_UTR_variant	Exon 3 of 3	1	NM_001110792.2	ENSP00000395535.2
MECP2	ENST00000303391.11	c.*8503delC		3_prime_UTR_variant	Exon 4 of 4	1	NM_004992.4	ENSP00000301948.6
MECP2	ENST00000630151.3	c.*8503delC		3_prime_UTR_variant	Exon 4 of 4	5		ENSP00000486089.2

Frequencies

GnomAD3 genomes AF: 0.0401 AC: 2902 AN: 72406 Hom.: 69 Cov.: 16

Gnomad AFR AF: 0.103

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0266

Gnomad ASJ AF: 0.00647

Gnomad EAS AF: 0.0318

Gnomad SAS AF: 0.0344

Gnomad FIN AF: 0.0450

Gnomad MID AF: 0.0281

Gnomad NFE AF: 0.00975

Gnomad OTH AF: 0.0300

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0403 AC: 6 AN: 149 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 49

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AC: 0 AN: 0

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AF: 0.0405 AC: 6 AN: 148

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AC: 0 AN: 0

Other (OTH) AF: 0.00 AC: 0 AN: 1

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000062), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.0400 AC: 2900 AN: 72429 Hom.: 69 Cov.: 16 AF XY: 0.0471 AC XY: 730 AN XY: 15491

African (AFR) AF: 0.103 AC: 2123 AN: 20590

American (AMR) AF: 0.0266 AC: 173 AN: 6504

Ashkenazi Jewish (ASJ) AF: 0.00647 AC: 12 AN: 1854

East Asian (EAS) AF: 0.0313 AC: 59 AN: 1885

South Asian (SAS) AF: 0.0334 AC: 36 AN: 1079

European-Finnish (FIN) AF: 0.0450 AC: 107 AN: 2376

Middle Eastern (MID) AF: 0.0305 AC: 5 AN: 164

European-Non Finnish (NFE) AF: 0.00975 AC: 356 AN: 36505

Other (OTH) AF: 0.0296 AC: 29 AN: 980

Alfa AF: 0.00364 Hom.: 36

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, single submitter

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). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.2
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs267608360; hg19: chrX-153287314; COSMIC: COSV57654346; COSMIC: COSV57654346;