X-154021863-TGG-TGGGG

Position:

• chrX-154021863-TGG-TGGGG

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BS1 BS2

The NM_001110792.2(MECP2):​c.*8502_*8503dupCC variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.0010 (0 hom., 8 hem., cov: 16)
  • Exomes 𝑓: 0.0 (0 hom. 0 hem.)
  • Failed GnomAD Quality Control
• Consequence: MECP2 NM_001110792.2 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.18

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]

ACMG classification

Verdict is Benign. Variant got -8 ACMG points.

• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00105 (76/72677) while in subpopulation AFR AF= 0.0017 (35/20627). AF 95% confidence interval is 0.00125. There are 0 homozygotes in gnomad4. There are 8 alleles in male gnomad4 subpopulation. Median coverage is 16. This position pass quality control queck.
• BS2: High Hemizygotes in GnomAd4 at 8 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MECP2	NM_001110792.2	c.*8502_*8503dupCC		3_prime_UTR_variant	3/3	ENST00000453960.7	NP_001104262.1
MECP2	NM_004992.4	c.*8502_*8503dupCC		3_prime_UTR_variant	4/4	ENST00000303391.11	NP_004983.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MECP2	ENST00000453960	c.*8502_*8503dupCC		3_prime_UTR_variant	3/3	1	NM_001110792.2	ENSP00000395535.2
MECP2	ENST00000303391	c.*8502_*8503dupCC		3_prime_UTR_variant	4/4	1	NM_004992.4	ENSP00000301948.6

Frequencies

GnomAD3 genomes AF: 0.00105 AC: 76 AN: 72651 Hom.: 0 Cov.: 16 AF XY: 0.000514 AC XY: 8 AN XY: 15567

Gnomad AFR AF: 0.00170

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000307

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00158

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00453

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000683

Gnomad OTH AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 182 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 64

Gnomad4 FIN exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.00105 AC: 76 AN: 72677 Hom.: 0 Cov.: 16 AF XY: 0.000513 AC XY: 8 AN XY: 15583

Gnomad4 AFR AF: 0.00170

Gnomad4 AMR AF: 0.000306

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00159

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00453

Gnomad4 NFE AF: 0.000683

Gnomad4 OTH AF: 0.00

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs267608360; hg19: chrX-153287314;