NM_001110792.2:c.45_47delAGG

Variant names:

• chrX-154097618-GCCT-G
• rs587783744
• NM_001110792.2:c.45_47delAGG

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP3 BP6_Very_Strong BS2

The NM_001110792.2(MECP2):​c.45_47delAGG​(p.Gly16del) variant causes a disruptive inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000404 in 1,019,857 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 6 hemizygotes in GnomAD. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. G15G) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000048 (0 hom., 1 hem., cov: 20)
  • Exomes 𝑓: 0.00044 (0 hom. 5 hem.)
• Consequence: MECP2 NM_001110792.2 disruptive_inframe_deletion
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 3.07
• 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 -13 ACMG points.

• BP3: Nonframeshift variant in repetitive region in NM_001110792.2
• BP6: Variant X-154097618-GCCT-G is Benign according to our data. Variant chrX-154097618-GCCT-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 517006.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAd4 at 5 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_47delAGG	p.Gly16del	disruptive_inframe_deletion	Exon 1 of 3	NP_001104262.1	A0A140VKC4
	MECP2	NM_004992.4	MANE Plus Clinical	c.-116_-114delAGG		5_prime_UTR	Exon 1 of 4	NP_004983.1	D3YJ43
	MECP2	NM_001316337.2		c.-563_-561delAGG		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_47delAGG	p.Gly16del	disruptive_inframe_deletion	Exon 1 of 3	ENSP00000395535.2	P51608-2
	MECP2	ENST00000303391.11	TSL:1 MANE Plus Clinical	c.-116_-114delAGG		5_prime_UTR	Exon 1 of 4	ENSP00000301948.6	P51608-1
	MECP2	ENST00000631210.1	TSL:1	n.305+7160_305+7162delAGG		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.0000480 AC: 5 AN: 104172 Hom.: 0 Cov.: 20

Gnomad AFR AF: 0.0000345

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000988

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000639

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000199

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00138 AC: 99 AN: 71845 AF XY: 0.000107

Gnomad AFR exome AF: 0.000685

Gnomad AMR exome AF: 0.00146

Gnomad ASJ exome AF: 0.00377

Gnomad EAS exome AF: 0.000846

Gnomad FIN exome AF: 0.00190

Gnomad NFE exome AF: 0.00124

Gnomad OTH exome AF: 0.00123

GnomAD4 exome AF: 0.000444 AC: 407 AN: 915645 Hom.: 0 AF XY: 0.0000179 AC XY: 5 AN XY: 279779

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.000551 AC: 11 AN: 19981

American (AMR) AF: 0.00166 AC: 33 AN: 19891

Ashkenazi Jewish (ASJ) AF: 0.00132 AC: 18 AN: 13648

East Asian (EAS) AF: 0.000467 AC: 10 AN: 21396

South Asian (SAS) AF: 0.00102 AC: 34 AN: 33311

European-Finnish (FIN) AF: 0.00132 AC: 28 AN: 21147

Middle Eastern (MID) AF: 0.000318 AC: 1 AN: 3148

European-Non Finnish (NFE) AF: 0.000335 AC: 250 AN: 746547

Other (OTH) AF: 0.000601 AC: 22 AN: 36576

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.0000480 AC: 5 AN: 104212 Hom.: 0 Cov.: 20 AF XY: 0.0000347 AC XY: 1 AN XY: 28838

African (AFR) AF: 0.0000344 AC: 1 AN: 29028

American (AMR) AF: 0.0000987 AC: 1 AN: 10133

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

East Asian (EAS) AF: 0.000642 AC: 2 AN: 3117

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

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 4683

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

European-Non Finnish (NFE) AF: 0.0000199 AC: 1 AN: 50128

Other (OTH) AF: 0.00 AC: 0 AN: 1439

Alfa AF: 0.00267 Hom.: 6

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		3.1
Mutation Taster		=73/27	polymorphism

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: rs587783744; hg19: chrX-153363075; COSMIC: COSV100318666; COSMIC: COSV100318666;