rs2071569

Variant names:

• chrX-154031524-G-A
• rs2071569
• NM_001110792.2:c.414-74C>T

Your query was ambiguous. Multiple possible variants found:

• chrX-154031524-G-A
• chrX-154031524-G-C
• chrX-154031524-G-T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001110792.2(MECP2):​c.414-74C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.018 in 1,132,367 control chromosomes in the GnomAD database, including 1,757 homozygotes. There are 6,272 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.018 (133 hom., 694 hem., cov: 23)
  • Exomes 𝑓: 0.018 (1624 hom. 5578 hem.)
• Consequence: MECP2 NM_001110792.2 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4 O:1
• Conservation: PhyloP100: -0.111
• Publications: 2 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=-0.9).
• BP6: Variant X-154031524-G-A is Benign according to our data. Variant chrX-154031524-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 156072.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-154031524-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 156072.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-154031524-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 156072.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-154031524-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 156072.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-154031524-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 156072.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-154031524-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 156072.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-154031524-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 156072.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-154031524-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 156072.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-154031524-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 156072.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-154031524-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 156072.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-154031524-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 156072.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-154031524-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 156072.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-154031524-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 156072.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-154031524-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 156072.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-154031524-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 156072.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-154031524-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 156072.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-154031524-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 156072.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-154031524-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 156072.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.269 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MECP2	NM_001110792.2	c.414-74C>T		intron_variant	Intron 2 of 2	ENST00000453960.7	NP_001104262.1
MECP2	NM_004992.4	c.378-74C>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.414-74C>T		intron_variant	Intron 2 of 2	1	NM_001110792.2	ENSP00000395535.2
MECP2	ENST00000303391.11	c.378-74C>T		intron_variant	Intron 3 of 3	1	NM_004992.4	ENSP00000301948.6

Frequencies

GnomAD3 genomes AF: 0.0182 AC: 2031 AN: 111782 Hom.: 133 Cov.: 23

Gnomad AFR AF: 0.00224

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0763

Gnomad ASJ AF: 0.000756

Gnomad EAS AF: 0.283

Gnomad SAS AF: 0.0119

Gnomad FIN AF: 0.00344

Gnomad MID AF: 0.00837

Gnomad NFE AF: 0.00128

Gnomad OTH AF: 0.0240

GnomAD4 exome AF: 0.0180 AC: 18327 AN: 1020530 Hom.: 1624 AF XY: 0.0185 AC XY: 5578 AN XY: 302320

African (AFR) AF: 0.00148 AC: 37 AN: 24960

American (AMR) AF: 0.151 AC: 5256 AN: 34864

Ashkenazi Jewish (ASJ) AF: 0.000424 AC: 8 AN: 18887

East Asian (EAS) AF: 0.354 AC: 10594 AN: 29928

South Asian (SAS) AF: 0.0108 AC: 564 AN: 52038

European-Finnish (FIN) AF: 0.00550 AC: 209 AN: 37996

Middle Eastern (MID) AF: 0.00448 AC: 13 AN: 2902

European-Non Finnish (NFE) AF: 0.00114 AC: 885 AN: 775404

Other (OTH) AF: 0.0175 AC: 761 AN: 43551

GnomAD4 genome AF: 0.0181 AC: 2028 AN: 111837 Hom.: 133 Cov.: 23 AF XY: 0.0204 AC XY: 694 AN XY: 34019

African (AFR) AF: 0.00224 AC: 69 AN: 30810

American (AMR) AF: 0.0761 AC: 806 AN: 10587

Ashkenazi Jewish (ASJ) AF: 0.000756 AC: 2 AN: 2646

East Asian (EAS) AF: 0.284 AC: 993 AN: 3499

South Asian (SAS) AF: 0.0116 AC: 31 AN: 2678

European-Finnish (FIN) AF: 0.00344 AC: 21 AN: 6096

Middle Eastern (MID) AF: 0.00917 AC: 2 AN: 218

European-Non Finnish (NFE) AF: 0.00128 AC: 68 AN: 53097

Other (OTH) AF: 0.0237 AC: 36 AN: 1521

Alfa AF: 0.00652 Hom.: 47

Bravo AF: 0.0307

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

Mar 03, 2015

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

- -

-

RettBASE

Significance: not provided

Review Status: flagged submission

Collection Method: literature only

- -

not specified Benign:1

Jun 12, 2013

RettBASE

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: curation

- -

Rett syndrome Benign:1

Aug 14, 2023

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 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	0.076
DANN	Benign	0.49
PhyloP100		-0.11
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: rs2071569; hg19: chrX-153296975; COSMIC: COSV57651739; COSMIC: COSV57651739;