rs56036177

Positions:

• chrX-154026890-C-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_001110792.2(MECP2):​c.*3477G>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 0.00351 in 111,664 control chromosomes in the GnomAD database, including 2 homozygotes. There are 104 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0035 (2 hom., 104 hem., cov: 23)
  • Exomes 𝑓: 0.0060 (0 hom. 0 hem.)
• Consequence: MECP2 NM_001110792.2 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:2
• Conservation: PhyloP100: -1.85

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]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant X-154026890-C-T is Benign according to our data. Variant chrX-154026890-C-T is described in ClinVar as [Benign]. Clinvar id is 143261.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-154026890-C-T is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0035 (390/111330) while in subpopulation NFE AF= 0.00553 (293/52940). AF 95% confidence interval is 0.00501. There are 2 homozygotes in gnomad4. There are 104 alleles in male gnomad4 subpopulation. Median coverage is 23. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 2 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MECP2	NM_001110792.2	c.*3477G>A		3_prime_UTR_variant	3/3	ENST00000453960.7	NP_001104262.1
MECP2	NM_004992.4	c.*3477G>A		3_prime_UTR_variant	4/4	ENST00000303391.11	NP_004983.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MECP2	ENST00000303391.11	c.*3477G>A		3_prime_UTR_variant	4/4	1	NM_004992.4	ENSP00000301948	P1
MECP2	ENST00000453960.7	c.*3477G>A		3_prime_UTR_variant	3/3	1	NM_001110792.2	ENSP00000395535

Frequencies

GnomAD3 genomes AF: 0.00351 AC: 391 AN: 111277 Hom.: 2 Cov.: 23 AF XY: 0.00310 AC XY: 104 AN XY: 33507

Gnomad AFR AF: 0.000786

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00484

Gnomad ASJ AF: 0.000757

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00219

Gnomad MID AF: 0.00417

Gnomad NFE AF: 0.00555

Gnomad OTH AF: 0.00402

GnomAD4 exome AF: 0.00599 AC: 2 AN: 334 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 132

Gnomad4 FIN exome AF: 0.00338

Gnomad4 NFE exome AF: 0.0303

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.00350 AC: 390 AN: 111330 Hom.: 2 Cov.: 23 AF XY: 0.00310 AC XY: 104 AN XY: 33570

Gnomad4 AFR AF: 0.000784

Gnomad4 AMR AF: 0.00483

Gnomad4 ASJ AF: 0.000757

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00219

Gnomad4 NFE AF: 0.00553

Gnomad4 OTH AF: 0.00397

Alfa AF: 0.00459 Hom.: 26

Bravo AF: 0.00320

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Benign, no assertion criteria provided

curation

RettBASE

Mar 10, 2010

- -

Rett syndrome Benign:1

Benign, criteria provided, single submitter

curation

Centre for Population Genomics, CPG

Aug 14, 2023

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). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.023
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: rs56036177; hg19: chrX-153292341;