rs61753982

Variant names:

• chrX-154031466-GA-G
• rs61753982
• NM_001110792.2:c.414-17delT

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.414-17delT variant causes a intron change. The variant allele was found at a frequency of 0.00563 in 1,209,376 control chromosomes in the GnomAD database, including 19 homozygotes. There are 2,150 hemizygotes in GnomAD. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0044 (3 hom., 145 hem., cov: 22)
  • Exomes 𝑓: 0.0058 (16 hom. 2005 hem.)
• Consequence: MECP2 NM_001110792.2 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:12 O:1
• Conservation: PhyloP100: 4.81
• 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: Benign. The variant received -16 ACMG points.

• BP6: Variant X-154031466-GA-G is Benign according to our data. Variant chrX-154031466-GA-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 156063.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00438 (492/112275) while in subpopulation NFE AF = 0.0066 (351/53189). AF 95% confidence interval is 0.00603. There are 3 homozygotes in GnomAd4. There are 145 alleles in the male GnomAd4 subpopulation. Median coverage is 22. This position passed quality control check.
• BS2: High AC in GnomAd4 at 492 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.414-17delT		intron	N/A	NP_001104262.1	A0A140VKC4
	MECP2	NM_004992.4	MANE Plus Clinical	c.378-17delT		intron	N/A	NP_004983.1	D3YJ43
	MECP2	NM_001316337.2		c.99-17delT		intron	N/A	NP_001303266.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MECP2	ENST00000453960.7	TSL:1 MANE Select	c.414-17delT		intron	N/A	ENSP00000395535.2	P51608-2
	MECP2	ENST00000303391.11	TSL:1 MANE Plus Clinical	c.378-17delT		intron	N/A	ENSP00000301948.6	P51608-1
	MECP2	ENST00000630151.3	TSL:5	c.378-17delT		intron	N/A	ENSP00000486089.2	P51608-1

Frequencies

GnomAD3 genomes AF: 0.00438 AC: 492 AN: 112221 Hom.: 3 Cov.: 22

Gnomad AFR AF: 0.000745

Gnomad AMI AF: 0.00293

Gnomad AMR AF: 0.00377

Gnomad ASJ AF: 0.00679

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00767

Gnomad MID AF: 0.00417

Gnomad NFE AF: 0.00660

Gnomad OTH AF: 0.00663

GnomAD2 exomes AF: 0.00432 AC: 782 AN: 181154 AF XY: 0.00408

Gnomad AFR exome AF: 0.000614

Gnomad AMR exome AF: 0.00252

Gnomad ASJ exome AF: 0.00522

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0117

Gnomad NFE exome AF: 0.00567

Gnomad OTH exome AF: 0.00601

GnomAD4 exome AF: 0.00576 AC: 6319 AN: 1097101 Hom.: 16 Cov.: 33 AF XY: 0.00553 AC XY: 2005 AN XY: 362565

African (AFR) AF: 0.000417 AC: 11 AN: 26387

American (AMR) AF: 0.00287 AC: 101 AN: 35206

Ashkenazi Jewish (ASJ) AF: 0.00609 AC: 118 AN: 19380

East Asian (EAS) AF: 0.00 AC: 0 AN: 30203

South Asian (SAS) AF: 0.00 AC: 0 AN: 54107

European-Finnish (FIN) AF: 0.0111 AC: 449 AN: 40469

Middle Eastern (MID) AF: 0.00101 AC: 4 AN: 3966

European-Non Finnish (NFE) AF: 0.00647 AC: 5445 AN: 841332

Other (OTH) AF: 0.00415 AC: 191 AN: 46051

GnomAD4 genome AF: 0.00438 AC: 492 AN: 112275 Hom.: 3 Cov.: 22 AF XY: 0.00421 AC XY: 145 AN XY: 34441

African (AFR) AF: 0.000743 AC: 23 AN: 30953

American (AMR) AF: 0.00376 AC: 40 AN: 10629

Ashkenazi Jewish (ASJ) AF: 0.00679 AC: 18 AN: 2652

East Asian (EAS) AF: 0.00 AC: 0 AN: 3586

South Asian (SAS) AF: 0.00 AC: 0 AN: 2712

European-Finnish (FIN) AF: 0.00767 AC: 47 AN: 6124

Middle Eastern (MID) AF: 0.00457 AC: 1 AN: 219

European-Non Finnish (NFE) AF: 0.00660 AC: 351 AN: 53189

Other (OTH) AF: 0.00654 AC: 10 AN: 1528

Alfa AF: 0.00523 Hom.: 43

Bravo AF: 0.00430

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not provided (6)
-	-	3	not specified (3)
-	-	2	Rett syndrome (2)
-	-	1	Inborn genetic diseases (1)
-	-	1	Severe neonatal-onset encephalopathy with microcephaly (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		4.8
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: rs61753982; hg19: chrX-153296917; COSMIC: COSV57654424; COSMIC: COSV57654424;