X-154029489-G-C

Variant names:

• chrX-154029489-G-C
• rs3027924
• NM_001110792.2:c.*878C>G

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.*878C>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.164 in 111,571 control chromosomes in the GnomAD database, including 1,777 homozygotes. There are 4,921 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.16 (1776 hom., 4893 hem., cov: 23)
  • Exomes 𝑓: 0.11 (1 hom. 28 hem.)
• Consequence: MECP2 NM_001110792.2 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.809
• Publications: 4 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=-0.81).
• BP6: Variant X-154029489-G-C is Benign according to our data. Variant chrX-154029489-G-C is described in ClinVar as Benign. ClinVar VariationId is 143292.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.354 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001110792.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MECP2	NM_001110792.2	MANE Select	c.*878C>G		3_prime_UTR	Exon 3 of 3	NP_001104262.1
	MECP2	NM_004992.4	MANE Plus Clinical	c.*878C>G		3_prime_UTR	Exon 4 of 4	NP_004983.1
	MECP2	NM_001316337.2		c.*878C>G		3_prime_UTR	Exon 5 of 5	NP_001303266.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MECP2	ENST00000453960.7	TSL:1 MANE Select	c.*878C>G		3_prime_UTR	Exon 3 of 3	ENSP00000395535.2
	MECP2	ENST00000303391.11	TSL:1 MANE Plus Clinical	c.*878C>G		3_prime_UTR	Exon 4 of 4	ENSP00000301948.6
	MECP2	ENST00000630151.3	TSL:5	c.*878C>G		3_prime_UTR	Exon 4 of 4	ENSP00000486089.2

Frequencies

GnomAD3 genomes AF: 0.164 AC: 18229 AN: 111031 Hom.: 1771 Cov.: 23

Gnomad AFR AF: 0.360

Gnomad AMI AF: 0.0414

Gnomad AMR AF: 0.0888

Gnomad ASJ AF: 0.0756

Gnomad EAS AF: 0.0127

Gnomad SAS AF: 0.0316

Gnomad FIN AF: 0.0766

Gnomad MID AF: 0.112

Gnomad NFE AF: 0.101

Gnomad OTH AF: 0.150

GnomAD4 exome AF: 0.114 AC: 55 AN: 484 Hom.: 1 Cov.: 0 AF XY: 0.177 AC XY: 28 AN XY: 158

African (AFR) AF: 1.00 AC: 1 AN: 1

American (AMR) AF: 0.100 AC: 1 AN: 10

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 1

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AF: 0.00 AC: 0 AN: 5

European-Finnish (FIN) AF: 0.115 AC: 34 AN: 295

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3

European-Non Finnish (NFE) AF: 0.123 AC: 19 AN: 155

Other (OTH) AF: 0.00 AC: 0 AN: 14

GnomAD4 genome AF: 0.164 AC: 18260 AN: 111087 Hom.: 1776 Cov.: 23 AF XY: 0.147 AC XY: 4893 AN XY: 33391

African (AFR) AF: 0.360 AC: 10928 AN: 30344

American (AMR) AF: 0.0885 AC: 942 AN: 10640

Ashkenazi Jewish (ASJ) AF: 0.0756 AC: 200 AN: 2646

East Asian (EAS) AF: 0.0124 AC: 44 AN: 3545

South Asian (SAS) AF: 0.0306 AC: 82 AN: 2680

European-Finnish (FIN) AF: 0.0766 AC: 461 AN: 6018

Middle Eastern (MID) AF: 0.104 AC: 22 AN: 212

European-Non Finnish (NFE) AF: 0.101 AC: 5315 AN: 52816

Other (OTH) AF: 0.158 AC: 238 AN: 1509

Alfa AF: 0.0526 Hom.: 278

Bravo AF: 0.178

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)
-	-	1	not specified (1)
-	-	1	Rett syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	3.2
DANN	Benign	0.76
PhyloP100		0.81
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: rs3027924; hg19: chrX-153294940;