X-154030744-G-C

Variant names:

• chrX-154030744-G-C
• rs782171742
• NM_001110792.2:c.1120C>G

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_Moderate BP6_Moderate BS2

The NM_001110792.2(MECP2):​c.1120C>G​(p.Pro374Ala) variant causes a missense change. The variant allele was found at a frequency of 0.0000207 in 1,208,365 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 6 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.000036 (0 hom., 1 hem., cov: 22)
  • Exomes 𝑓: 0.000019 (0 hom. 5 hem.)
• Consequence: MECP2 NM_001110792.2 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 4.86

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 -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.19181323).
• BP6: Variant X-154030744-G-C is Benign according to our data. Variant chrX-154030744-G-C is described in ClinVar as [Benign]. Clinvar id is 468729.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Hemizygotes in GnomAdExome4 at 5 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MECP2	NM_001110792.2	c.1120C>G	p.Pro374Ala	missense_variant	Exon 3 of 3	ENST00000453960.7	NP_001104262.1
MECP2	NM_004992.4	c.1084C>G	p.Pro362Ala	missense_variant	Exon 4 of 4	ENST00000303391.11	NP_004983.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MECP2	ENST00000453960.7	c.1120C>G	p.Pro374Ala	missense_variant	Exon 3 of 3	1	NM_001110792.2	ENSP00000395535.2
MECP2	ENST00000303391.11	c.1084C>G	p.Pro362Ala	missense_variant	Exon 4 of 4	1	NM_004992.4	ENSP00000301948.6
MECP2	ENST00000407218	c.*456C>G		3_prime_UTR_variant	Exon 4 of 4	5		ENSP00000384865.2
MECP2	ENST00000628176	c.*456C>G		3_prime_UTR_variant	Exon 5 of 5	3		ENSP00000486978.1

Frequencies

GnomAD3 genomes AF: 0.0000360 AC: 4 AN: 110966 Hom.: 0 Cov.: 22 AF XY: 0.0000302 AC XY: 1 AN XY: 33162

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000758

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00000554 AC: 1 AN: 180544 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 66320

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000124

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000191 AC: 21 AN: 1097399 Hom.: 0 Cov.: 35 AF XY: 0.0000138 AC XY: 5 AN XY: 362895

Gnomad4 AFR exome AF: 0.0000379

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: 0.0000238

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000360 AC: 4 AN: 110966 Hom.: 0 Cov.: 22 AF XY: 0.0000302 AC XY: 1 AN XY: 33162

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000758

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000113

ExAC AF: 0.00000824 AC: 1

EpiCase AF: 0.00

EpiControl AF: 0.0000595

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Severe neonatal-onset encephalopathy with microcephaly Benign:1

Jul 16, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.053
BayesDel_addAF	Uncertain	0.085	D
BayesDel_noAF	Benign	-0.12
CADD	Benign	19
DANN	Benign	0.94
DEOGEN2	Benign	0.26	T;.
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Uncertain	0.88	D;D
M_CAP	Pathogenic	0.34	D
MetaRNN	Benign	0.19	T;T
MetaSVM	Benign	-0.45	T
MutationAssessor	Benign	1.4	L;.
PrimateAI	Uncertain	0.57	T
PROVEAN	Benign	-0.26	N;N
REVEL	Uncertain	0.36
Sift	Benign	0.031	D;D
Sift4G	Benign	0.24	T;T
Polyphen		0.036	B;B
Vest4		0.19
MutPred		0.26		Loss of glycosylation at P362 (P = 0.011);.;
MVP		0.62
ClinPred		0.13	T
GERP RS		5.1
Varity_R		0.10
gMVP		0.59

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: rs782171742; hg19: chrX-153296195;