rs3027931

Positions:

• chrX-154031691-G-A
• chrX-154031691-G-C
• chrX-154031691-G-T

Variant summary

Our verdict is Benign. Variant got -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

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -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 id is 156064.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-154031691-G-A is described in Lovd as [Benign].
• 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 male gnomad4 subpopulation. Median coverage is 23. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 40 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MECP2	NM_001110792.2	c.414-241C>T		intron_variant		ENST00000453960.7	NP_001104262.1
MECP2	NM_004992.4	c.378-241C>T		intron_variant		ENST00000303391.11	NP_004983.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MECP2	ENST00000453960.7	c.414-241C>T		intron_variant		1	NM_001110792.2	ENSP00000395535.2
MECP2	ENST00000303391.11	c.378-241C>T		intron_variant		1	NM_004992.4	ENSP00000301948.6

Frequencies

GnomAD3 genomes AF: 0.0252 AC: 2810 AN: 111382 Hom.: 40 Cov.: 23 AF XY: 0.0271 AC XY: 910 AN XY: 33536

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

Gnomad4 AFR AF: 0.00420

Gnomad4 AMR AF: 0.0406

Gnomad4 ASJ AF: 0.0144

Gnomad4 EAS AF: 0.000280

Gnomad4 SAS AF: 0.0389

Gnomad4 FIN AF: 0.0532

Gnomad4 NFE AF: 0.0332

Gnomad4 OTH AF: 0.0211

Alfa AF: 0.0125 Hom.: 58

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

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 23, 2018	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
not provided, flagged submission	literature only	RettBASE	-	- -

not specified Benign:1

Benign, no assertion criteria provided

curation

RettBASE

Sep 05, 2002

- -

Rett syndrome Benign:1

Benign, criteria provided, single submitter

curation

Centre for Population Genomics, CPG

Mar 18, 2024

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

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: rs3027931; hg19: chrX-153297142;