NM_001110792.2:c.*489G>C

Variant names:

• chrX-154029878-C-G
• rs111565519
• NM_001110792.2:c.*489G>C

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BS1 BS2

The NM_001110792.2(MECP2):​c.*489G>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00602 in 213,395 control chromosomes in the GnomAD database, including 6 homozygotes. There are 379 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0051 (3 hom., 156 hem., cov: 23)
  • Exomes 𝑓: 0.0070 (3 hom. 223 hem.)
• Consequence: MECP2 NM_001110792.2 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.618
• Publications: 0 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 -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.43).
• BP6: Variant X-154029878-C-G is Benign according to our data. Variant chrX-154029878-C-G is described in ClinVar as Benign. ClinVar VariationId is 143273.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 = 0.00514 (578/112347) while in subpopulation NFE AF = 0.00764 (406/53167). AF 95% confidence interval is 0.00702. There are 3 homozygotes in GnomAd4. There are 156 alleles in the male GnomAd4 subpopulation. Median coverage is 23. This position passed quality control check.
• BS2: High AC in GnomAd4 at 578 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.*489G>C		3_prime_UTR	Exon 3 of 3	NP_001104262.1	A0A140VKC4
	MECP2	NM_004992.4	MANE Plus Clinical	c.*489G>C		3_prime_UTR	Exon 4 of 4	NP_004983.1	D3YJ43
	MECP2	NM_001316337.2		c.*489G>C		3_prime_UTR	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.*489G>C		3_prime_UTR	Exon 3 of 3	ENSP00000395535.2	P51608-2
	MECP2	ENST00000303391.11	TSL:1 MANE Plus Clinical	c.*489G>C		3_prime_UTR	Exon 4 of 4	ENSP00000301948.6	P51608-1
	MECP2	ENST00000630151.3	TSL:5	c.*489G>C		3_prime_UTR	Exon 4 of 4	ENSP00000486089.2	P51608-1

Frequencies

GnomAD3 genomes AF: 0.00514 AC: 577 AN: 112295 Hom.: 2 Cov.: 23

Gnomad AFR AF: 0.000908

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00692

Gnomad ASJ AF: 0.00829

Gnomad EAS AF: 0.000835

Gnomad SAS AF: 0.00624

Gnomad FIN AF: 0.00113

Gnomad MID AF: 0.0209

Gnomad NFE AF: 0.00764

Gnomad OTH AF: 0.00994

GnomAD4 exome AF: 0.00700 AC: 707 AN: 101048 Hom.: 3 Cov.: 0 AF XY: 0.00724 AC XY: 223 AN XY: 30790

African (AFR) AF: 0.000299 AC: 1 AN: 3339

American (AMR) AF: 0.00307 AC: 13 AN: 4231

Ashkenazi Jewish (ASJ) AF: 0.00759 AC: 19 AN: 2504

East Asian (EAS) AF: 0.000464 AC: 2 AN: 4311

South Asian (SAS) AF: 0.0104 AC: 139 AN: 13374

European-Finnish (FIN) AF: 0.00203 AC: 10 AN: 4930

Middle Eastern (MID) AF: 0.0193 AC: 7 AN: 362

European-Non Finnish (NFE) AF: 0.00781 AC: 490 AN: 62760

Other (OTH) AF: 0.00496 AC: 26 AN: 5237

GnomAD4 genome AF: 0.00514 AC: 578 AN: 112347 Hom.: 3 Cov.: 23 AF XY: 0.00452 AC XY: 156 AN XY: 34503

African (AFR) AF: 0.000906 AC: 28 AN: 30920

American (AMR) AF: 0.00692 AC: 74 AN: 10700

Ashkenazi Jewish (ASJ) AF: 0.00829 AC: 22 AN: 2653

East Asian (EAS) AF: 0.000838 AC: 3 AN: 3580

South Asian (SAS) AF: 0.00626 AC: 17 AN: 2714

European-Finnish (FIN) AF: 0.00113 AC: 7 AN: 6181

Middle Eastern (MID) AF: 0.0275 AC: 6 AN: 218

European-Non Finnish (NFE) AF: 0.00764 AC: 406 AN: 53167

Other (OTH) AF: 0.00982 AC: 15 AN: 1528

Alfa AF: 0.00567 Hom.: 32

Bravo AF: 0.00612

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.43
CADD	Benign	6.8
DANN	Benign	0.82
PhyloP100		0.62
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: rs111565519; hg19: chrX-153295329;