rs2734647

Positions:

• chrX-154026729-T-C

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BA1

The NM_001110792.2(MECP2):​c.*3638A>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. Variant has been reported in Lovd as Likely benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.83 (28176 hom., 26347 hem., cov: 23)
  • Exomes 𝑓: 0.88 (77 hom. 131 hem.)
  • Failed GnomAD Quality Control
• Consequence: MECP2 NM_001110792.2 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.815

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]

ACMG classification

Verdict is Benign. Variant got -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.58).
• BP6: Variant X-154026729-T-C is Benign according to our data. Variant chrX-154026729-T-C is described in Lovd as [Likely_benign].
• BA1: GnomAdExome4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.61 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MECP2	NM_001110792.2	c.*3638A>G		3_prime_UTR_variant	3/3	ENST00000453960.7
MECP2	NM_004992.4	c.*3638A>G		3_prime_UTR_variant	4/4	ENST00000303391.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MECP2	ENST00000303391.11	c.*3638A>G		3_prime_UTR_variant	4/4	1	NM_004992.4	P1
MECP2	ENST00000453960.7	c.*3638A>G		3_prime_UTR_variant	3/3	1	NM_001110792.2

Frequencies

GnomAD3 genomes AF: 0.827 AC: 91325 AN: 110435 Hom.: 28174 Cov.: 23 AF XY: 0.806 AC XY: 26286 AN XY: 32609

Gnomad AFR AF: 0.951

Gnomad AMI AF: 0.963

Gnomad AMR AF: 0.617

Gnomad ASJ AF: 0.782

Gnomad EAS AF: 0.240

Gnomad SAS AF: 0.393

Gnomad FIN AF: 0.857

Gnomad MID AF: 0.711

Gnomad NFE AF: 0.857

Gnomad OTH AF: 0.769

GnomAD4 exome AF: 0.875 AC: 309 AN: 353 Hom.: 77 Cov.: 0 AF XY: 0.868 AC XY: 131 AN XY: 151

Gnomad4 AFR exome AF: 1.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.500

Gnomad4 EAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.890

Gnomad4 NFE exome AF: 0.829

Gnomad4 OTH exome AF: 0.833

GnomAD4 genome Data not reliable, filtered out with message: InbreedingCoeff AF: 0.827 AC: 91383 AN: 110489 Hom.: 28176 Cov.: 23 AF XY: 0.806 AC XY: 26347 AN XY: 32673

Gnomad4 AFR AF: 0.951

Gnomad4 AMR AF: 0.616

Gnomad4 ASJ AF: 0.782

Gnomad4 EAS AF: 0.240

Gnomad4 SAS AF: 0.395

Gnomad4 FIN AF: 0.857

Gnomad4 NFE AF: 0.857

Gnomad4 OTH AF: 0.769

Alfa AF: 0.824 Hom.: 49966

Bravo AF: 0.814

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.58
CADD	Benign	12
DANN	Benign	0.81

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

Publications

LitVar

Other links and lift over

dbSNP: rs2734647; hg19: chrX-153292180; COSMIC: COSV57653495; COSMIC: COSV57653495;