rs61752980

Variant names:

• chrX-154030691-G-A
• rs61752980
• NM_001110792.2:c.1173C>T

Your query was ambiguous. Multiple possible variants found:

• chrX-154030691-G-A
• chrX-154030691-G-T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_001110792.2(MECP2):​c.1173C>T​(p.Pro391Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000219 in 1,201,914 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 105 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. P391P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00019 (0 hom., 8 hem., cov: 22)
  • Exomes 𝑓: 0.00022 (0 hom. 97 hem.)
• Consequence: MECP2 NM_001110792.2 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: -0.245
• 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: 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.98).
• BP6: Variant X-154030691-G-A is Benign according to our data. Variant chrX-154030691-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 95185.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.245 with no splicing effect.
• BS1: Variant frequency is greater than expected in population mid. GnomAdExome4 allele frequency = 0.000222 (242/1092169) while in subpopulation MID AF = 0.00135 (5/3704). AF 95% confidence interval is 0.000532. There are 0 homozygotes in GnomAdExome4. There are 97 alleles in the male GnomAdExome4 subpopulation. Median coverage is 35. This position passed quality control check.
• BS2: High AC in GnomAd4 at 21 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MECP2	NM_001110792.2	MANE Select	c.1173C>T	p.Pro391Pro	synonymous	Exon 3 of 3	NP_001104262.1
	MECP2	NM_004992.4	MANE Plus Clinical	c.1137C>T	p.Pro379Pro	synonymous	Exon 4 of 4	NP_004983.1
	MECP2	NM_001316337.2		c.858C>T	p.Pro286Pro	synonymous	Exon 5 of 5	NP_001303266.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MECP2	ENST00000453960.7	TSL:1 MANE Select	c.1173C>T	p.Pro391Pro	synonymous	Exon 3 of 3	ENSP00000395535.2
	MECP2	ENST00000303391.11	TSL:1 MANE Plus Clinical	c.1137C>T	p.Pro379Pro	synonymous	Exon 4 of 4	ENSP00000301948.6
	MECP2	ENST00000630151.3	TSL:5	c.1137C>T	p.Pro379Pro	synonymous	Exon 4 of 4	ENSP00000486089.2

Frequencies

GnomAD3 genomes AF: 0.000191 AC: 21 AN: 109745 Hom.: 0 Cov.: 22

Gnomad AFR AF: 0.0000664

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000578

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.000286

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000168

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000153

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000345 AC: 60 AN: 173766 AF XY: 0.000353

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000406

Gnomad ASJ exome AF: 0.00126

Gnomad EAS exome AF: 0.0000733

Gnomad FIN exome AF: 0.0000713

Gnomad NFE exome AF: 0.000363

Gnomad OTH exome AF: 0.000693

GnomAD4 exome AF: 0.000222 AC: 242 AN: 1092169 Hom.: 0 Cov.: 35 AF XY: 0.000270 AC XY: 97 AN XY: 359061

African (AFR) AF: 0.000114 AC: 3 AN: 26253

American (AMR) AF: 0.000371 AC: 13 AN: 35018

Ashkenazi Jewish (ASJ) AF: 0.00161 AC: 31 AN: 19274

East Asian (EAS) AF: 0.00 AC: 0 AN: 30148

South Asian (SAS) AF: 0.000408 AC: 22 AN: 53860

European-Finnish (FIN) AF: 0.0000260 AC: 1 AN: 38440

Middle Eastern (MID) AF: 0.00135 AC: 5 AN: 3704

European-Non Finnish (NFE) AF: 0.000179 AC: 150 AN: 839636

Other (OTH) AF: 0.000371 AC: 17 AN: 45836

GnomAD4 genome AF: 0.000191 AC: 21 AN: 109745 Hom.: 0 Cov.: 22 AF XY: 0.000250 AC XY: 8 AN XY: 31953

African (AFR) AF: 0.0000664 AC: 2 AN: 30108

American (AMR) AF: 0.000578 AC: 6 AN: 10385

Ashkenazi Jewish (ASJ) AF: 0.00115 AC: 3 AN: 2614

East Asian (EAS) AF: 0.000286 AC: 1 AN: 3499

South Asian (SAS) AF: 0.00 AC: 0 AN: 2500

European-Finnish (FIN) AF: 0.000168 AC: 1 AN: 5948

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 239

European-Non Finnish (NFE) AF: 0.000153 AC: 8 AN: 52298

Other (OTH) AF: 0.00 AC: 0 AN: 1475

Alfa AF: 0.000260 Hom.: 2

Bravo AF: 0.000351

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	2	not specified (2)
-	-	1	History of neurodevelopmental disorder (1)
-	-	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
BayesDel_noAF	Benign	-0.98
CADD	Benign	0.042
DANN	Benign	0.33
PhyloP100		-0.24
Mutation Taster		=100/0	polymorphism

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: rs61752980; hg19: chrX-153296142; COSMIC: COSV57655046; COSMIC: COSV57655046;