X-154097709-A-AGC

Variant names:

• chrX-154097709-A-AGC
• rs782107551
• NM_001110792.2:c.-46_-45dupGC

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BS2

The NM_001110792.2(MECP2):​c.-46_-45dupGC variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000156 in 897,402 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 3 hemizygotes in GnomAD. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.000019 (0 hom., 1 hem., cov: 21)
  • Exomes 𝑓: 0.000015 (0 hom. 2 hem.)
• Consequence: MECP2 NM_001110792.2 5_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.54
• Publications: 0 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: Likely_benign. The variant received -4 ACMG points.

• BS2: High AC in GnomAdExome4 at 12 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MECP2	NM_001110792.2	MANE Select	c.-46_-45dupGC		5_prime_UTR	Exon 1 of 3	NP_001104262.1
	MECP2	NM_004992.4	MANE Plus Clinical	c.-206_-205dupGC		5_prime_UTR	Exon 1 of 4	NP_004983.1
	MECP2	NM_001316337.2		c.-653_-652dupGC		5_prime_UTR	Exon 1 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.-46_-45dupGC		5_prime_UTR	Exon 1 of 3	ENSP00000395535.2
	MECP2	ENST00000303391.11	TSL:1 MANE Plus Clinical	c.-206_-205dupGC		5_prime_UTR	Exon 1 of 4	ENSP00000301948.6
	MECP2	ENST00000631210.1	TSL:1	n.305+7070_305+7071dupGC		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.0000189 AC: 2 AN: 105673 Hom.: 0 Cov.: 21

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.000388

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000197

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000389 AC: 1 AN: 25701 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000692

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000152 AC: 12 AN: 791729 Hom.: 0 Cov.: 28 AF XY: 0.00000867 AC XY: 2 AN XY: 230639

African (AFR) AF: 0.00 AC: 0 AN: 16695

American (AMR) AF: 0.00 AC: 0 AN: 7659

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 8432

East Asian (EAS) AF: 0.0000593 AC: 1 AN: 16871

South Asian (SAS) AF: 0.0000561 AC: 1 AN: 17812

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 13579

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2327

European-Non Finnish (NFE) AF: 0.0000147 AC: 10 AN: 678200

Other (OTH) AF: 0.00 AC: 0 AN: 30154

GnomAD4 genome AF: 0.0000189 AC: 2 AN: 105673 Hom.: 0 Cov.: 21 AF XY: 0.0000333 AC XY: 1 AN XY: 30021

African (AFR) AF: 0.00 AC: 0 AN: 29368

American (AMR) AF: 0.00 AC: 0 AN: 10211

Ashkenazi Jewish (ASJ) AF: 0.000388 AC: 1 AN: 2577

East Asian (EAS) AF: 0.00 AC: 0 AN: 3298

South Asian (SAS) AF: 0.00 AC: 0 AN: 2526

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 4631

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 228

European-Non Finnish (NFE) AF: 0.0000197 AC: 1 AN: 50807

Other (OTH) AF: 0.00 AC: 0 AN: 1402

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		3.5

Splicing

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

Other links and lift over

dbSNP: rs782107551; hg19: chrX-153363166;