rs61750248

Variant names:

• chrX-154030994-G-A
• rs61750248
• NM_001110792.2:c.870C>T

Your query was ambiguous. Multiple possible variants found:

• chrX-154030994-G-A
• chrX-154030994-G-C

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.870C>T​(p.Ala290Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000359 in 1,210,218 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 158 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00044 (0 hom., 11 hem., cov: 24)
  • Exomes 𝑓: 0.00035 (0 hom. 147 hem.)
• Consequence: MECP2 NM_001110792.2 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: -4.36
• 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant X-154030994-G-A is Benign according to our data. Variant chrX-154030994-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 143709.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-4.36 with no splicing effect.
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.000437 (49/112104) while in subpopulation EAS AF = 0.00254 (9/3543). AF 95% confidence interval is 0.00132. There are 0 homozygotes in GnomAd4. There are 11 alleles in the male GnomAd4 subpopulation. Median coverage is 24. This position passed quality control check.
• BS2: High AC in GnomAd4 at 49 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.870C>T	p.Ala290Ala	synonymous	Exon 3 of 3	NP_001104262.1	A0A140VKC4
	MECP2	NM_004992.4	MANE Plus Clinical	c.834C>T	p.Ala278Ala	synonymous	Exon 4 of 4	NP_004983.1	D3YJ43
	MECP2	NM_001316337.2		c.555C>T	p.Ala185Ala	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.870C>T	p.Ala290Ala	synonymous	Exon 3 of 3	ENSP00000395535.2	P51608-2
	MECP2	ENST00000303391.11	TSL:1 MANE Plus Clinical	c.834C>T	p.Ala278Ala	synonymous	Exon 4 of 4	ENSP00000301948.6	P51608-1
	MECP2	ENST00000630151.3	TSL:5	c.834C>T	p.Ala278Ala	synonymous	Exon 4 of 4	ENSP00000486089.2	P51608-1

Frequencies

GnomAD3 genomes AF: 0.000437 AC: 49 AN: 112050 Hom.: 0 Cov.: 24

Gnomad AFR AF: 0.000649

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000936

Gnomad ASJ AF: 0.000378

Gnomad EAS AF: 0.00253

Gnomad SAS AF: 0.000368

Gnomad FIN AF: 0.000164

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000301

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000489 AC: 89 AN: 181911 AF XY: 0.000549

Gnomad AFR exome AF: 0.000876

Gnomad AMR exome AF: 0.000474

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00217

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000321

Gnomad OTH exome AF: 0.000667

GnomAD4 exome AF: 0.000352 AC: 386 AN: 1098114 Hom.: 0 Cov.: 35 AF XY: 0.000404 AC XY: 147 AN XY: 363514

African (AFR) AF: 0.000341 AC: 9 AN: 26401

American (AMR) AF: 0.000398 AC: 14 AN: 35204

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19386

East Asian (EAS) AF: 0.00281 AC: 85 AN: 30206

South Asian (SAS) AF: 0.000185 AC: 10 AN: 54147

European-Finnish (FIN) AF: 0.000149 AC: 6 AN: 40402

Middle Eastern (MID) AF: 0.000484 AC: 2 AN: 4135

European-Non Finnish (NFE) AF: 0.000284 AC: 239 AN: 842140

Other (OTH) AF: 0.000456 AC: 21 AN: 46093

GnomAD4 genome AF: 0.000437 AC: 49 AN: 112104 Hom.: 0 Cov.: 24 AF XY: 0.000321 AC XY: 11 AN XY: 34282

African (AFR) AF: 0.000648 AC: 20 AN: 30885

American (AMR) AF: 0.0000935 AC: 1 AN: 10696

Ashkenazi Jewish (ASJ) AF: 0.000378 AC: 1 AN: 2649

East Asian (EAS) AF: 0.00254 AC: 9 AN: 3543

South Asian (SAS) AF: 0.000369 AC: 1 AN: 2709

European-Finnish (FIN) AF: 0.000164 AC: 1 AN: 6106

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 218

European-Non Finnish (NFE) AF: 0.000301 AC: 16 AN: 53087

Other (OTH) AF: 0.00 AC: 0 AN: 1525

Alfa AF: 0.000347 Hom.: 2

Bravo AF: 0.000412

EpiCase AF: 0.000382

EpiControl AF: 0.000593

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not provided (5)
-	-	3	not specified (3)
-	-	1	Inborn genetic diseases (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	-0.90
CADD	Benign	0.0080
DANN	Benign	0.74
PhyloP100		-4.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Mutation Taster		=98/2	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: rs61750248; hg19: chrX-153296445; COSMIC: COSV57657600; COSMIC: COSV57657600;