chrX-154031691-G-A

Variant names:

• chrX-154031691-G-A
• rs3027931
• NM_001110792.2:c.414-241C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001110792.2(MECP2):​c.414-241C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0252 in 111,434 control chromosomes in the GnomAD database, including 40 homozygotes. There are 911 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency: Genomes: 𝑓 0.025 (40 hom., 911 hem., cov: 23)
• Consequence: MECP2 NM_001110792.2 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4 O:1
• Conservation: PhyloP100: -0.486
• Publications: 1 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BP6: Variant X-154031691-G-A is Benign according to our data. Variant chrX-154031691-G-A is described in ClinVar as Benign. ClinVar VariationId is 156064.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.0252 (2811/111434) while in subpopulation AMR AF = 0.0406 (427/10512). AF 95% confidence interval is 0.0374. There are 40 homozygotes in GnomAd4. There are 911 alleles in the male GnomAd4 subpopulation. Median coverage is 23. This position passed quality control check.
• BS2: High AC in GnomAd4 at 2811 XL,Unknown,AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MECP2	NM_001110792.2	c.414-241C>T		intron_variant	Intron 2 of 2	ENST00000453960.7	NP_001104262.1
MECP2	NM_004992.4	c.378-241C>T		intron_variant	Intron 3 of 3	ENST00000303391.11	NP_004983.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MECP2	ENST00000453960.7	c.414-241C>T		intron_variant	Intron 2 of 2	1	NM_001110792.2	ENSP00000395535.2
MECP2	ENST00000303391.11	c.378-241C>T		intron_variant	Intron 3 of 3	1	NM_004992.4	ENSP00000301948.6

Frequencies

GnomAD3 genomes AF: 0.0252 AC: 2810 AN: 111382 Hom.: 40 Cov.: 23

Gnomad AFR AF: 0.00421

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0407

Gnomad ASJ AF: 0.0144

Gnomad EAS AF: 0.000279

Gnomad SAS AF: 0.0383

Gnomad FIN AF: 0.0532

Gnomad MID AF: 0.0293

Gnomad NFE AF: 0.0332

Gnomad OTH AF: 0.0213

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

GnomAD4 genome AF: 0.0252 AC: 2811 AN: 111434 Hom.: 40 Cov.: 23 AF XY: 0.0271 AC XY: 911 AN XY: 33598

African (AFR) AF: 0.00420 AC: 129 AN: 30688

American (AMR) AF: 0.0406 AC: 427 AN: 10512

Ashkenazi Jewish (ASJ) AF: 0.0144 AC: 38 AN: 2647

East Asian (EAS) AF: 0.000280 AC: 1 AN: 3575

South Asian (SAS) AF: 0.0389 AC: 102 AN: 2625

European-Finnish (FIN) AF: 0.0532 AC: 317 AN: 5960

Middle Eastern (MID) AF: 0.0274 AC: 6 AN: 219

European-Non Finnish (NFE) AF: 0.0332 AC: 1759 AN: 53006

Other (OTH) AF: 0.0211 AC: 32 AN: 1518

Alfa AF: 0.00964 Hom.: 78

Bravo AF: 0.0219

ClinVar

Significance: Benign

Submissions summary: Benign:4 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2 Other:1

-

RettBASE

Significance: not provided

Review Status: flagged submission

Collection Method: literature only

- -

Jun 23, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

not specified Benign:1

Sep 05, 2002

RettBASE

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: curation

- -

Rett syndrome Benign:1

Mar 18, 2024

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 3.0, 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 3.0 (BA1). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.51
DANN	Benign	0.67
PhyloP100		-0.49
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: rs3027931; hg19: chrX-153297142;