rs267608370

Variant names:

• chrX-154030377-C-G
• rs267608370
• NM_001110792.2:c.1487G>C

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BS1 BS2

The NM_001110792.2(MECP2):​c.1487G>C​(p.Arg496Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000248 in 1,210,034 control chromosomes in the GnomAD database, including 1 homozygotes. There are 11 hemizygotes in GnomAD. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.000018 (0 hom., 0 hem., cov: 23)
  • Exomes 𝑓: 0.000025 (1 hom. 11 hem.)
• Consequence: MECP2 NM_001110792.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 3.38
• 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 -16 ACMG points.

• BP6: Variant X-154030377-C-G is Benign according to our data. Variant chrX-154030377-C-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 143483.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population mid. GnomAdExome4 allele frequency = 0.0000255 (28/1098239) while in subpopulation MID AF = 0.00411 (17/4134). AF 95% confidence interval is 0.00262. There are 1 homozygotes in GnomAdExome4. There are 11 alleles in the male GnomAdExome4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAdExome4 at 28 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.1487G>C	p.Arg496Thr	missense	Exon 3 of 3	NP_001104262.1	A0A140VKC4
	MECP2	NM_004992.4	MANE Plus Clinical	c.1451G>C	p.Arg484Thr	missense	Exon 4 of 4	NP_004983.1	D3YJ43
	MECP2	NM_001316337.2		c.1172G>C	p.Arg391Thr	missense	Exon 5 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.1487G>C	p.Arg496Thr	missense	Exon 3 of 3	ENSP00000395535.2	P51608-2
	MECP2	ENST00000303391.11	TSL:1 MANE Plus Clinical	c.1451G>C	p.Arg484Thr	missense	Exon 4 of 4	ENSP00000301948.6	P51608-1
	MECP2	ENST00000630151.3	TSL:5	c.1451G>C	p.Arg484Thr	missense	Exon 4 of 4	ENSP00000486089.2	P51608-1

Frequencies

GnomAD3 genomes AF: 0.0000179 AC: 2 AN: 111795 Hom.: 0 Cov.: 23

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.000378

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000188

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000436 AC: 8 AN: 183487 AF XY: 0.0000294

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: 0.0000732

Gnomad OTH exome AF: 0.000441

GnomAD4 exome AF: 0.0000255 AC: 28 AN: 1098239 Hom.: 1 Cov.: 32 AF XY: 0.0000303 AC XY: 11 AN XY: 363593

African (AFR) AF: 0.00 AC: 0 AN: 26403

American (AMR) AF: 0.00 AC: 0 AN: 35207

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19385

East Asian (EAS) AF: 0.00 AC: 0 AN: 30206

South Asian (SAS) AF: 0.0000369 AC: 2 AN: 54149

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40517

Middle Eastern (MID) AF: 0.00411 AC: 17 AN: 4134

European-Non Finnish (NFE) AF: 0.00000831 AC: 7 AN: 842142

Other (OTH) AF: 0.0000434 AC: 2 AN: 46096

GnomAD4 genome AF: 0.0000179 AC: 2 AN: 111795 Hom.: 0 Cov.: 23 AF XY: 0.00 AC XY: 0 AN XY: 33935

African (AFR) AF: 0.00 AC: 0 AN: 30738

American (AMR) AF: 0.00 AC: 0 AN: 10599

Ashkenazi Jewish (ASJ) AF: 0.000378 AC: 1 AN: 2645

East Asian (EAS) AF: 0.00 AC: 0 AN: 3568

South Asian (SAS) AF: 0.00 AC: 0 AN: 2621

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6120

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 238

European-Non Finnish (NFE) AF: 0.0000188 AC: 1 AN: 53068

Other (OTH) AF: 0.00 AC: 0 AN: 1516

Alfa AF: 0.000217 Hom.: 1

Bravo AF: 0.0000189

ExAC AF: 0.0000494 AC: 6

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	2	not specified (2)
-	-	1	MECP2-related disorder (1)
-	-	1	Rett syndrome (1)
-	-	1	Severe neonatal-onset encephalopathy with microcephaly (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.79
BayesDel_addAF	Uncertain	0.043	T
BayesDel_noAF	Pathogenic	0.27
CADD	Uncertain	24
DANN	Benign	0.93
DEOGEN2	Uncertain	0.45	T
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Uncertain	0.90	D
M_CAP	Pathogenic	0.88	D
MetaRNN	Uncertain	0.54	D
MetaSVM	Uncertain	0.46	D
MutationAssessor	Benign	0.97	L
PhyloP100		3.4
PrimateAI	Uncertain	0.77	T
PROVEAN	Benign	-0.24	N
REVEL	Uncertain	0.56
Sift	Uncertain	0.012	D
Sift4G	Uncertain	0.027	D
Polyphen		0.90	P
Vest4		0.46
MutPred		0.39		Gain of phosphorylation at R484 (P = 0.0248)
MVP		1.0
ClinPred		0.079	T
GERP RS		5.8
Varity_R		0.28
gMVP		0.37
Mutation Taster		=49/51	disease causing

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: rs267608370; hg19: chrX-153295828;