rs62621673

Positions:

• chrX-154030039-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.*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. Variant has been reported in ClinVar as Benign (★).

• 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
• Clinical Significance: Benign criteria provided, single submitter B:2
• Conservation: PhyloP100: 0.0790

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=-0.81).
• BP6: Variant X-154030039-C-T is Benign according to our data. Variant chrX-154030039-C-T is described in ClinVar as [Benign]. Clinvar id is 143260.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-154030039-C-T is described in Lovd as [Benign].
• 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 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	UniProt
MECP2	NM_001110792.2	c.*328G>A		3_prime_UTR_variant	3/3	ENST00000453960.7
MECP2	NM_004992.4	c.*328G>A		3_prime_UTR_variant	4/4	ENST00000303391.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MECP2	ENST00000303391.11	c.*328G>A		3_prime_UTR_variant	4/4	1	NM_004992.4	P1
MECP2	ENST00000453960.7	c.*328G>A		3_prime_UTR_variant	3/3	1	NM_001110792.2

Frequencies

GnomAD3 genomes AF: 0.00469 AC: 519 AN: 110694 Hom.: 2 Cov.: 23 AF XY: 0.00455 AC XY: 150 AN XY: 32944

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

Gnomad4 AFR exome AF: 0.00183

Gnomad4 AMR exome AF: 0.00202

Gnomad4 ASJ exome AF: 0.00527

Gnomad4 EAS exome AF: 0.000542

Gnomad4 SAS exome AF: 0.00135

Gnomad4 FIN exome AF: 0.00891

Gnomad4 NFE exome AF: 0.00612

Gnomad4 OTH exome AF: 0.00356

GnomAD4 genome AF: 0.00469 AC: 519 AN: 110748 Hom.: 2 Cov.: 23 AF XY: 0.00454 AC XY: 150 AN XY: 33008

Gnomad4 AFR AF: 0.00227

Gnomad4 AMR AF: 0.00201

Gnomad4 ASJ AF: 0.00646

Gnomad4 EAS AF: 0.000286

Gnomad4 SAS AF: 0.00268

Gnomad4 FIN AF: 0.00793

Gnomad4 NFE AF: 0.00655

Gnomad4 OTH AF: 0.00526

Alfa AF: 0.00565 Hom.: 29

Bravo AF: 0.00427

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, single submitter

Submissions by phenotype

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). The variant is observed in at least 2 individuals with no features of Rett Syndrome (BS2). -

not specified Benign:1

Benign, no assertion criteria provided

curation

RettBASE

Mar 10, 2010

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	0.83
DANN	Benign	0.88

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: rs62621673; hg19: chrX-153295490; COSMIC: COSV100318122; COSMIC: COSV100318122;