19-16576649-T-C

Position:

• chr19-16576649-T-C

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_004831.5(MED26):​c.1181A>G​(p.Lys394Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: MED26 NM_004831.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.98

Genes affected

MED26 (HGNC:2376): (mediator complex subunit 26) The activation of gene transcription is a multistep process that is triggered by factors that recognize transcriptional enhancer sites in DNA. These factors work with co-activators to direct transcriptional initiation by the RNA polymerase II apparatus. The protein encoded by this gene is a subunit of the CRSP (cofactor required for SP1 activation) complex, which, along with TFIID, is required for efficient activation by SP1. This protein is also a component of other multisubunit complexes e.g. thyroid hormone receptor-(TR-) associated proteins which interact with TR and facilitate TR function on DNA templates in conjunction with initiation factors and cofactors. [provided by RefSeq, Jul 2008]

ENSG00000141979 (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.04206255).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MED26	NM_004831.5	c.1181A>G	p.Lys394Arg	missense_variant	3/3	ENST00000263390.8	NP_004822.2
LOC105372295	XR_936359.3	n.475-1517T>C		intron_variant
LOC105372295	XR_936360.3	n.260-1517T>C		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MED26	ENST00000263390.8	c.1181A>G	p.Lys394Arg	missense_variant	3/3	1	NM_004831.5	ENSP00000263390.3
MED26	ENST00000611692.4	c.*546A>G		3_prime_UTR_variant	4/4	1		ENSP00000484490.1
ENSG00000141979	ENST00000409035.1	n.1205A>G		non_coding_transcript_exon_variant	4/12	2		ENSP00000386951.2
MED26	ENST00000597244.1	n.2129A>G		non_coding_transcript_exon_variant	1/1	6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 01, 2024

The c.1181A>G (p.K394R) alteration is located in exon 3 (coding exon 3) of the MED26 gene. This alteration results from a A to G substitution at nucleotide position 1181, causing the lysine (K) at amino acid position 394 to be replaced by an arginine (R). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.087
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.59
CADD	Benign	17
DANN	Benign	0.67
DEOGEN2	Benign	0.060	T
Eigen	Benign	-0.48
Eigen_PC	Benign	-0.33
FATHMM_MKL	Benign	0.76	D
LIST_S2	Benign	0.67	T
M_CAP	Benign	0.0058	T
MetaRNN	Benign	0.042	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.14	N
PrimateAI	Uncertain	0.53	T
PROVEAN	Benign	-0.33	N
REVEL	Benign	0.082
Sift	Benign	0.68	T
Sift4G	Benign	0.85	T
Polyphen		0.0010	B
Vest4		0.12
MutPred		0.13		Loss of methylation at K394 (P = 0.0222);
MVP		0.13
MPC		0.26
ClinPred		0.26	T
GERP RS		4.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Varity_R		0.081
gMVP		0.066

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr19-16687460;