rs1555801968

Variant names:

• chr19-49828536-GC-CT
• rs1555801968
• NM_030973.4:c.393_394delGCinsCT

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_030973.4(MED25):​c.393_394delGCinsCT​(p.MetArg131IleCys) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: MED25 NM_030973.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.58

Genes affected

MED25 (HGNC:28845): (mediator complex subunit 25) This gene encodes a component of the transcriptional coactivator complex termed the Mediator complex. This complex is required for transcription of most RNA polymerase II-dependent genes. The encoded protein plays a role in chromatin modification and in preinitiation complex assembly. Mutations in this gene are associated with Charcot-Marie-Tooth disease type 2B2. [provided by RefSeq, Apr 2010]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MED25	NM_030973.4	c.393_394delGCinsCT	p.MetArg131IleCys	missense_variant		ENST00000312865.10	NP_112235.2
MED25	NM_001378355.1	c.393_394delGCinsCT	p.MetArg131IleCys	missense_variant			NP_001365284.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MED25	ENST00000312865.10	c.393_394delGCinsCT	p.MetArg131IleCys	missense_variant		1	NM_030973.4	ENSP00000326767.5
MED25	ENST00000595185.5	c.393_394delGCinsCT	p.MetArg131IleCys	missense_variant		1		ENSP00000470027.1
MED25	ENST00000538643.5	c.181-1975_181-1974delGCinsCT		intron_variant	Intron 2 of 12	1		ENSP00000437496.1
MED25	ENST00000593767.3	c.393_394delGCinsCT	p.MetArg131IleCys	missense_variant		3		ENSP00000470692.3

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Charcot-Marie-Tooth disease type 2 Uncertain:1

May 23, 2017

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with a MED25-related disease. In summary, this variant has uncertain impact on MED25 function. The available evidence is currently insufficient to determine its role in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Experimental studies and prediction algorithms are not available for this variant, and the functional significance of the disrupted amino acids is currently unknown. This variant, c.393_394delGCinsCT, results in the deletion and insertion of 2 amino acids in the MED25 protein (p.Met131_Arg132delinsIleCys), but otherwise preserves the integrity of the reading frame. -

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1555801968; hg19: chr19-50331793;