rs1060499622

Positions:

• chrX-154030680-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PM1 PM2 BP4

The NM_001110792.2(MECP2):​c.1184T>C​(p.Leu395Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000924 in 1,081,850 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 11/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L395F) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 19)
  • Exomes 𝑓: 9.2e-7 (0 hom. 1 hem.)
• Consequence: MECP2 NM_001110792.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.04

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 Uncertain_significance. Variant got 3 ACMG points.

• PM1: In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 14 benign, 11 uncertain in NM_001110792.2
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.4019434).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MECP2	NM_001110792.2	c.1184T>C	p.Leu395Pro	missense_variant	3/3	ENST00000453960.7
MECP2	NM_004992.4	c.1148T>C	p.Leu383Pro	missense_variant	4/4	ENST00000303391.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MECP2	ENST00000453960.7	c.1184T>C	p.Leu395Pro	missense_variant	3/3	1	NM_001110792.2
MECP2	ENST00000303391.11	c.1148T>C	p.Leu383Pro	missense_variant	4/4	1	NM_004992.4	P1
MECP2	ENST00000407218.5	c.*520T>C		3_prime_UTR_variant	4/4	5
MECP2	ENST00000628176.2	c.*520T>C		3_prime_UTR_variant	5/5	3

Frequencies

GnomAD3 genomes Cov.: 19

GnomAD4 exome AF: 9.24e-7 AC: 1 AN: 1081850 Hom.: 0 Cov.: 35 AF XY: 0.00000284 AC XY: 1 AN XY: 352302

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000120

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 19

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Rett syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Molecular Diagnostics Lab, Nemours Children's Health, Delaware

Jul 14, 2015

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.076
BayesDel_addAF	Uncertain	0.026	T
BayesDel_noAF	Benign	-0.20
CADD	Benign	16
DANN	Benign	0.79
DEOGEN2	Benign	0.31	T;.
FATHMM_MKL	Benign	0.50	N
LIST_S2	Benign	0.81	T;T
M_CAP	Pathogenic	0.79	D
MetaRNN	Benign	0.40	T;T
MetaSVM	Uncertain	-0.11	T
MutationAssessor	Benign	-0.34	N;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.57	T
PROVEAN	Benign	-0.75	N;N
REVEL	Uncertain	0.39
Sift	Benign	0.26	T;T
Sift4G	Benign	0.30	T;T
Polyphen		0.97	D;D
Vest4		0.19
MutPred		0.32		Gain of glycosylation at L383 (P = 0.0107);.;
MVP		0.91
ClinPred		0.68	D
GERP RS		4.2
Varity_R		0.16
gMVP		0.45

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: rs1060499622; hg19: chrX-153296131; COSMIC: COSV105147176; COSMIC: COSV105147176;