rs5986954

Variant names:

• chrX-154083842-A-G
• rs5986954
• NM_001110792.2:c.62+13762T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001110792.2(MECP2):​c.62+13762T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0805 in 110,977 control chromosomes in the GnomAD database, including 501 homozygotes. There are 2,334 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.080 (501 hom., 2334 hem., cov: 21)
• Consequence: MECP2 NM_001110792.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.37
• Publications: 3 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.181 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.62+13762T>C		intron	N/A	NP_001104262.1
	MECP2	NM_004992.4	MANE Plus Clinical	c.26+8342T>C		intron	N/A	NP_004983.1
	MECP2	NM_001316337.2		c.-422+8342T>C		intron	N/A	NP_001303266.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MECP2	ENST00000453960.7	TSL:1 MANE Select	c.62+13762T>C		intron	N/A	ENSP00000395535.2
	MECP2	ENST00000303391.11	TSL:1 MANE Plus Clinical	c.26+8342T>C		intron	N/A	ENSP00000301948.6
	MECP2	ENST00000496908.5	TSL:1	n.157+12971T>C		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.0803 AC: 8904 AN: 110923 Hom.: 498 Cov.: 21

Gnomad AFR AF: 0.185

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0461

Gnomad ASJ AF: 0.0212

Gnomad EAS AF: 0.0119

Gnomad SAS AF: 0.0236

Gnomad FIN AF: 0.0414

Gnomad MID AF: 0.0250

Gnomad NFE AF: 0.0431

Gnomad OTH AF: 0.0710

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.0805 AC: 8932 AN: 110977 Hom.: 501 Cov.: 21 AF XY: 0.0703 AC XY: 2334 AN XY: 33209

African (AFR) AF: 0.185 AC: 5636 AN: 30391

American (AMR) AF: 0.0460 AC: 482 AN: 10472

Ashkenazi Jewish (ASJ) AF: 0.0212 AC: 56 AN: 2639

East Asian (EAS) AF: 0.0116 AC: 41 AN: 3529

South Asian (SAS) AF: 0.0236 AC: 63 AN: 2665

European-Finnish (FIN) AF: 0.0414 AC: 248 AN: 5986

Middle Eastern (MID) AF: 0.0274 AC: 6 AN: 219

European-Non Finnish (NFE) AF: 0.0431 AC: 2278 AN: 52881

Other (OTH) AF: 0.0807 AC: 122 AN: 1512

Alfa AF: 0.0703 Hom.: 418

Bravo AF: 0.0873

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.35
DANN	Benign	0.43
PhyloP100		-2.4
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: rs5986954; hg19: chrX-153349295;