rs62621674

Positions:

• chrX-154030008-C-G
• chrX-154030008-C-T

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_Moderate BP6_Moderate BS2

The ENST00000453960.7(MECP2):​c.*359G>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000157 in 285,983 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 14 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.00019 (0 hom., 9 hem., cov: 23)
  • Exomes 𝑓: 0.00014 (0 hom. 5 hem.)
• Consequence: MECP2 ENST00000453960.7 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:2
• Conservation: PhyloP100: 2.19

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 -8 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.44).
• BP6: Variant X-154030008-C-G is Benign according to our data. Variant chrX-154030008-C-G is described in ClinVar as [Benign]. Clinvar id is 143262.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-154030008-C-G is described in Lovd as [Benign].
• BS2: High Hemizygotes in GnomAd4 at 9 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MECP2	NM_001110792.2	c.*359G>C		3_prime_UTR_variant	3/3	ENST00000453960.7	NP_001104262.1
MECP2	NM_004992.4	c.*359G>C		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.*359G>C		3_prime_UTR_variant	4/4	1	NM_004992.4	ENSP00000301948	P1
MECP2	ENST00000453960.7	c.*359G>C		3_prime_UTR_variant	3/3	1	NM_001110792.2	ENSP00000395535

Frequencies

GnomAD3 genomes AF: 0.000188 AC: 21 AN: 111510 Hom.: 0 Cov.: 23 AF XY: 0.000267 AC XY: 9 AN XY: 33688

Gnomad AFR AF: 0.0000980

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000190

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000753

Gnomad FIN AF: 0.000164

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000208

Gnomad OTH AF: 0.00132

GnomAD4 exome AF: 0.000138 AC: 24 AN: 174418 Hom.: 0 Cov.: 0 AF XY: 0.0000880 AC XY: 5 AN XY: 56826

Gnomad4 AFR exome AF: 0.000180

Gnomad4 AMR exome AF: 0.000108

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000426

Gnomad4 FIN exome AF: 0.000712

Gnomad4 NFE exome AF: 0.000143

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.000188 AC: 21 AN: 111565 Hom.: 0 Cov.: 23 AF XY: 0.000267 AC XY: 9 AN XY: 33753

Gnomad4 AFR AF: 0.0000978

Gnomad4 AMR AF: 0.000190

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000755

Gnomad4 FIN AF: 0.000164

Gnomad4 NFE AF: 0.000208

Gnomad4 OTH AF: 0.00131

Bravo AF: 0.000166

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 v3 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). -

not specified Benign:1

Benign, no assertion criteria provided

curation

RettBASE

Nov 01, 2007

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.44
CADD	Benign	13
DANN	Benign	0.82

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: rs62621674; hg19: chrX-153295459;