rs786205046

Variant names:

• chrX-154097617-C-T
• rs786205046
• NM_001110792.2:c.49G>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 0P and 0B.

The NM_001110792.2(MECP2):​c.49G>A​(p.Glu17Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0000093 (0 hom., 0 hem., cov: 20)
  • Exomes 𝑓: 0.0 (0 hom. 0 hem.)
  • Failed GnomAD Quality Control
• Consequence: MECP2 NM_001110792.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:2
• Conservation: PhyloP100: 3.15
• Publications: 1 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: Uncertain_significance. The variant received 0 ACMG points.

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.49G>A	p.Glu17Lys	missense	Exon 1 of 3	NP_001104262.1	A0A140VKC4
	MECP2	NM_004992.4	MANE Plus Clinical	c.-112G>A		5_prime_UTR	Exon 1 of 4	NP_004983.1	D3YJ43
	MECP2	NM_001316337.2		c.-559G>A		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.49G>A	p.Glu17Lys	missense	Exon 1 of 3	ENSP00000395535.2	P51608-2
	MECP2	ENST00000303391.11	TSL:1 MANE Plus Clinical	c.-112G>A		5_prime_UTR	Exon 1 of 4	ENSP00000301948.6	P51608-1
	MECP2	ENST00000631210.1	TSL:1	n.305+7164G>A		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.00000931 AC: 1 AN: 107377 Hom.: 0 Cov.: 20

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000196

Gnomad OTH AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 942414 Hom.: 0 Cov.: 26 AF XY: 0.00 AC XY: 0 AN XY: 293168

African (AFR) AF: 0.00 AC: 0 AN: 20649

American (AMR) AF: 0.00 AC: 0 AN: 20955

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 14586

East Asian (EAS) AF: 0.00 AC: 0 AN: 22700

South Asian (SAS) AF: 0.00 AC: 0 AN: 35057

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 22646

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3313

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 764456

Other (OTH) AF: 0.00 AC: 0 AN: 38052

GnomAD4 genome AF: 0.00000931 AC: 1 AN: 107377 Hom.: 0 Cov.: 20 AF XY: 0.00 AC XY: 0 AN XY: 30511

African (AFR) AF: 0.00 AC: 0 AN: 29825

American (AMR) AF: 0.00 AC: 0 AN: 10438

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2602

East Asian (EAS) AF: 0.00 AC: 0 AN: 3303

South Asian (SAS) AF: 0.00 AC: 0 AN: 2541

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 5281

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 223

European-Non Finnish (NFE) AF: 0.0000196 AC: 1 AN: 51071

Other (OTH) AF: 0.00 AC: 0 AN: 1465

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Rett syndrome (1)
-	1	-	X-linked intellectual disability-psychosis-macroorchidism syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.53
BayesDel_addAF	Benign	-0.0019	T
BayesDel_noAF	Benign	-0.24
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.063	T
FATHMM_MKL	Benign	0.30	N
LIST_S2	Benign	0.51	T
M_CAP	Pathogenic	1.0	D
MetaRNN	Uncertain	0.47	T
MetaSVM	Uncertain	0.37	D
PhyloP100		3.1
PrimateAI	Pathogenic	0.91	D
PROVEAN	Benign	0.0	N
REVEL	Uncertain	0.33
Sift	Benign	0.46	T
Sift4G	Benign	0.64	T
Polyphen		0.99	D
Vest4		0.40
MutPred		0.22		Gain of glycosylation at E17 (P = 0.0053)
MVP		0.92
ClinPred		0.95	D
GERP RS		3.9
PromoterAI		-0.0023	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
gMVP		0.32
Mutation Taster		=85/15	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs786205046; hg19: chrX-153363074;