rs3027928

Variant names:

• chrX-154030595-G-A
• rs3027928
• NM_001110792.2:c.1269C>T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001110792.2(MECP2):​c.1269C>T​(p.Ser423Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00975 in 1,204,764 control chromosomes in the GnomAD database, including 1,069 homozygotes. There are 3,208 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.018 (164 hom., 595 hem., cov: 22)
  • Exomes 𝑓: 0.0089 (905 hom. 2613 hem.)
• Consequence: MECP2 NM_001110792.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:13
• Conservation: PhyloP100: -0.187
• 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: 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.76).
• BP6: Variant X-154030595-G-A is Benign according to our data. Variant chrX-154030595-G-A is described in ClinVar as Benign. ClinVar VariationId is 95189.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.187 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.167 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MECP2	NM_001110792.2	MANE Select	c.1269C>T	p.Ser423Ser	synonymous	Exon 3 of 3	NP_001104262.1	A0A140VKC4
	MECP2	NM_004992.4	MANE Plus Clinical	c.1233C>T	p.Ser411Ser	synonymous	Exon 4 of 4	NP_004983.1	D3YJ43
	MECP2	NM_001316337.2		c.954C>T	p.Ser318Ser	synonymous	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.1269C>T	p.Ser423Ser	synonymous	Exon 3 of 3	ENSP00000395535.2	P51608-2
	MECP2	ENST00000303391.11	TSL:1 MANE Plus Clinical	c.1233C>T	p.Ser411Ser	synonymous	Exon 4 of 4	ENSP00000301948.6	P51608-1
	MECP2	ENST00000630151.3	TSL:5	c.1233C>T	p.Ser411Ser	synonymous	Exon 4 of 4	ENSP00000486089.2	P51608-1

Frequencies

GnomAD3 genomes AF: 0.0181 AC: 1966 AN: 108878 Hom.: 159 Cov.: 22

Gnomad AFR AF: 0.00449

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.173

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00259

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000306

Gnomad OTH AF: 0.0384

GnomAD2 exomes AF: 0.0392 AC: 7070 AN: 180207 AF XY: 0.0278

Gnomad AFR exome AF: 0.00376

Gnomad AMR exome AF: 0.248

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00144

Gnomad FIN exome AF: 0.0000702

Gnomad NFE exome AF: 0.000124

Gnomad OTH exome AF: 0.0453

GnomAD4 exome AF: 0.00891 AC: 9761 AN: 1095840 Hom.: 905 Cov.: 32 AF XY: 0.00722 AC XY: 2613 AN XY: 362120

African (AFR) AF: 0.00337 AC: 89 AN: 26397

American (AMR) AF: 0.248 AC: 8717 AN: 35201

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

East Asian (EAS) AF: 0.00937 AC: 283 AN: 30205

South Asian (SAS) AF: 0.0000554 AC: 3 AN: 54139

European-Finnish (FIN) AF: 0.0000783 AC: 3 AN: 38320

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4077

European-Non Finnish (NFE) AF: 0.000154 AC: 130 AN: 842041

Other (OTH) AF: 0.0116 AC: 536 AN: 46075

GnomAD4 genome AF: 0.0182 AC: 1983 AN: 108924 Hom.: 164 Cov.: 22 AF XY: 0.0190 AC XY: 595 AN XY: 31256

African (AFR) AF: 0.00455 AC: 136 AN: 29891

American (AMR) AF: 0.174 AC: 1766 AN: 10145

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2606

East Asian (EAS) AF: 0.00260 AC: 9 AN: 3461

South Asian (SAS) AF: 0.00 AC: 0 AN: 2444

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 5740

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 216

European-Non Finnish (NFE) AF: 0.000306 AC: 16 AN: 52274

Other (OTH) AF: 0.0379 AC: 56 AN: 1476

Alfa AF: 0.00972 Hom.: 120

Bravo AF: 0.0351

EpiCase AF: 0.000382

EpiControl AF: 0.000356

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not provided (5)
-	-	5	not specified (5)
-	-	1	History of neurodevelopmental 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
BayesDel_noAF	Benign	-0.76
CADD	Benign	2.2
DANN	Benign	0.67
PhyloP100		-0.19
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
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: rs3027928; hg19: chrX-153296046;