X-154097618-GCCTCCT-GCCTCCTCCT

Variant names:

• chrX-154097618-G-GCCT
• rs587783744
• NM_001110792.2:c.45_47dupAGG

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 0P and 17B. BP3 BP6_Very_Strong BS1 BS2

The NM_001110792.2(MECP2):​c.45_47dupAGG​(p.Gly16dup) variant causes a disruptive inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00182 in 1,028,331 control chromosomes in the GnomAD database, including 3 homozygotes. There are 420 hemizygotes in GnomAD. Variant has been reported in ClinVar as Benign (★★★). Synonymous variant affecting the same amino acid position (i.e. G16G) has been classified as Pathogenic.

• Frequency:
  • Genomes: 𝑓 0.0018 (0 hom., 38 hem., cov: 20)
  • Exomes 𝑓: 0.0018 (3 hom. 382 hem.)
• Consequence: MECP2 NM_001110792.2 disruptive_inframe_insertion
• Clinical Significance: Benign reviewed by expert panel U:1 B:9
• Conservation: PhyloP100: 1.66
• 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: Labcorp Genetics (formerly Invitae), ClinGen, Ambry Genetics, Orphanet, 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 -17 ACMG points.

• BP3: Nonframeshift variant in repetitive region in NM_001110792.2
• BP6: Variant X-154097618-G-GCCT is Benign according to our data. Variant chrX-154097618-G-GCCT is described in ClinVar as Benign. ClinVar VariationId is 158882.Status of the report is reviewed_by_expert_panel, 3 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00181 (189/104220) while in subpopulation AFR AF = 0.00331 (96/29030). AF 95% confidence interval is 0.00277. There are 0 homozygotes in GnomAd4. There are 38 alleles in the male GnomAd4 subpopulation. Median coverage is 20. This position passed quality control check.
• BS2: High AC in GnomAd4 at 189 XL,Unknown,AD gene.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MECP2	NM_001110792.2	MANE Select	c.45_47dupAGG	p.Gly16dup	disruptive_inframe_insertion	Exon 1 of 3	NP_001104262.1	A0A140VKC4
	MECP2	NM_004992.4	MANE Plus Clinical	c.-116_-114dupAGG		5_prime_UTR	Exon 1 of 4	NP_004983.1	D3YJ43
	MECP2	NM_001316337.2		c.-563_-561dupAGG		5_prime_UTR	Exon 1 of 5	NP_001303266.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MECP2	ENST00000453960.7	TSL:1 MANE Select	c.45_47dupAGG	p.Gly16dup	disruptive_inframe_insertion	Exon 1 of 3	ENSP00000395535.2	P51608-2
	MECP2	ENST00000303391.11	TSL:1 MANE Plus Clinical	c.-116_-114dupAGG		5_prime_UTR	Exon 1 of 4	ENSP00000301948.6	P51608-1
	MECP2	ENST00000631210.1	TSL:1	n.305+7160_305+7162dupAGG		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.00181 AC: 189 AN: 104180 Hom.: 0 Cov.: 20

Gnomad AFR AF: 0.00331

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000593

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000320

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00168

Gnomad OTH AF: 0.00141

GnomAD2 exomes AF: 0.000863 AC: 62 AN: 71845 AF XY: 0.000640

Gnomad AFR exome AF: 0.00297

Gnomad AMR exome AF: 0.000343

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000212

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00110

Gnomad OTH exome AF: 0.000617

GnomAD4 exome AF: 0.00182 AC: 1683 AN: 924111 Hom.: 3 Cov.: 26 AF XY: 0.00134 AC XY: 382 AN XY: 284099

African (AFR) AF: 0.00219 AC: 44 AN: 20131

American (AMR) AF: 0.000445 AC: 9 AN: 20246

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 13881

East Asian (EAS) AF: 0.0000924 AC: 2 AN: 21648

South Asian (SAS) AF: 0.00120 AC: 41 AN: 34159

European-Finnish (FIN) AF: 0.000186 AC: 4 AN: 21495

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3171

European-Non Finnish (NFE) AF: 0.00202 AC: 1518 AN: 752426

Other (OTH) AF: 0.00176 AC: 65 AN: 36954

GnomAD4 genome AF: 0.00181 AC: 189 AN: 104220 Hom.: 0 Cov.: 20 AF XY: 0.00132 AC XY: 38 AN XY: 28838

African (AFR) AF: 0.00331 AC: 96 AN: 29030

American (AMR) AF: 0.000592 AC: 6 AN: 10133

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2550

East Asian (EAS) AF: 0.000321 AC: 1 AN: 3117

South Asian (SAS) AF: 0.00 AC: 0 AN: 2321

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 4685

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 202

European-Non Finnish (NFE) AF: 0.00168 AC: 84 AN: 50132

Other (OTH) AF: 0.00139 AC: 2 AN: 1439

Alfa AF: 0.000359 Hom.: 6

ClinVar

ClinVar submissions

Significance: Benign

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	-	3	not specified (3)
-	-	2	Rett syndrome (2)
-	1	1	Severe neonatal-onset encephalopathy with microcephaly (2)
-	-	1	Inborn genetic diseases (1)
-	-	1	MECP2-related disorder (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.7
Mutation Taster		=78/22	polymorphism

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs587783744; hg19: chrX-153363075;