rs2075597

Variant names:

• chrX-154032185-G-C
• rs2075597
• NM_001110792.2:c.413+22C>G

Your query was ambiguous. Multiple possible variants found:

• chrX-154032185-G-C
• chrX-154032185-G-A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001110792.2(MECP2):​c.413+22C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00688 in 1,162,678 control chromosomes in the GnomAD database, including 231 homozygotes. There are 2,465 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0091 (23 hom., 357 hem., cov: 24)
  • Exomes 𝑓: 0.0066 (208 hom. 2108 hem.)
• Consequence: MECP2 NM_001110792.2 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5 O:1
• Conservation: PhyloP100: -0.426
• Publications: 4 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant X-154032185-G-C is Benign according to our data. Variant chrX-154032185-G-C is described in ClinVar as Benign. ClinVar VariationId is 156054.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0948 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.413+22C>G		intron	N/A	NP_001104262.1	A0A140VKC4
	MECP2	NM_004992.4	MANE Plus Clinical	c.377+22C>G		intron	N/A	NP_004983.1	D3YJ43
	MECP2	NM_001316337.2		c.98+22C>G		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.413+22C>G		intron	N/A	ENSP00000395535.2	P51608-2
	MECP2	ENST00000303391.11	TSL:1 MANE Plus Clinical	c.377+22C>G		intron	N/A	ENSP00000301948.6	P51608-1
	MECP2	ENST00000630151.3	TSL:5	c.377+22C>G		intron	N/A	ENSP00000486089.2	P51608-1

Frequencies

GnomAD3 genomes AF: 0.00911 AC: 1029 AN: 113000 Hom.: 24 Cov.: 24

Gnomad AFR AF: 0.00315

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0442

Gnomad ASJ AF: 0.000377

Gnomad EAS AF: 0.103

Gnomad SAS AF: 0.00648

Gnomad FIN AF: 0.00191

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000769

Gnomad OTH AF: 0.00920

GnomAD2 exomes AF: 0.0215 AC: 3920 AN: 182491 AF XY: 0.0166

Gnomad AFR exome AF: 0.00237

Gnomad AMR exome AF: 0.0809

Gnomad ASJ exome AF: 0.000134

Gnomad EAS exome AF: 0.104

Gnomad FIN exome AF: 0.00157

Gnomad NFE exome AF: 0.000727

Gnomad OTH exome AF: 0.0184

GnomAD4 exome AF: 0.00664 AC: 6971 AN: 1049624 Hom.: 208 Cov.: 26 AF XY: 0.00651 AC XY: 2108 AN XY: 323956

African (AFR) AF: 0.00133 AC: 34 AN: 25472

American (AMR) AF: 0.0743 AC: 2609 AN: 35124

Ashkenazi Jewish (ASJ) AF: 0.000314 AC: 6 AN: 19093

East Asian (EAS) AF: 0.109 AC: 3285 AN: 30010

South Asian (SAS) AF: 0.00468 AC: 248 AN: 52988

European-Finnish (FIN) AF: 0.00138 AC: 56 AN: 40451

Middle Eastern (MID) AF: 0.00201 AC: 8 AN: 3985

European-Non Finnish (NFE) AF: 0.000495 AC: 395 AN: 798024

Other (OTH) AF: 0.00742 AC: 330 AN: 44477

GnomAD4 genome AF: 0.00907 AC: 1025 AN: 113054 Hom.: 23 Cov.: 24 AF XY: 0.0101 AC XY: 357 AN XY: 35200

African (AFR) AF: 0.00314 AC: 98 AN: 31228

American (AMR) AF: 0.0439 AC: 471 AN: 10737

Ashkenazi Jewish (ASJ) AF: 0.000377 AC: 1 AN: 2656

East Asian (EAS) AF: 0.103 AC: 371 AN: 3585

South Asian (SAS) AF: 0.00614 AC: 17 AN: 2769

European-Finnish (FIN) AF: 0.00191 AC: 12 AN: 6291

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 219

European-Non Finnish (NFE) AF: 0.000769 AC: 41 AN: 53340

Other (OTH) AF: 0.00909 AC: 14 AN: 1540

Alfa AF: 0.00532 Hom.: 31

Bravo AF: 0.0145

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (4)
-	-	1	not specified (1)
-	-	1	Rett syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	0.080
DANN	Benign	0.63
PhyloP100		-0.43
PromoterAI		-0.0034	Neutral
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: rs2075597; hg19: chrX-153297636; COSMIC: COSV57655893; COSMIC: COSV57655893;