Genetic Variant MED16:p.Ser861Cys (chr19-868153-G-C) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_005481.3(MED16):c.2582C>G(p.Ser861Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000124 in 1,611,846 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/20 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. S861P) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000098 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000034 ( 0 hom. )

Consequence

MED16
NM_005481.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.0210

Variant links:

Genes affected

MED16 (HGNC:17556): (mediator complex subunit 16) Enables thyroid hormone receptor binding activity and transcription coactivator activity. Involved in positive regulation of transcription initiation from RNA polymerase II promoter. Located in membrane. Part of mediator complex. [provided by Alliance of Genome Resources, Apr 2022]

MED16 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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=0.03670463).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MED16	NM_005481.3 link	c.2582C>G	p.Ser861Cys	missense_variant	Exon 16 of 16	ENST00000325464.6	NP_005472.2	Q9Y2X0-1
MED16	XM_017026120.3 link	c.2375C>G	p.Ser792Cys	missense_variant	Exon 15 of 15		XP_016881609.1
MED16	XM_047438010.1 link	c.*220C>G		3_prime_UTR_variant	Exon 14 of 14		XP_047293966.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MED16	ENST00000325464.6 link	c.2582C>G	p.Ser861Cys	missense_variant	Exon 16 of 16	5	NM_005481.3	ENSP00000325612.1		Q9Y2X0-1

Frequencies

GnomAD3 genomes

AF:

0.0000920

AC:

AN:

152252

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000338

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000290

AC:

AN:

241382

Hom.:

AF XY:

0.0000152

AC XY:

AN XY:

131640

show subpopulations

Gnomad AFR exome

AF:

0.000452

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:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000343

AC:

AN:

1459476

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

725978

show subpopulations

Gnomad4 AFR exome

AF:

0.000149

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:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000984

AC:

AN:

152370

Hom.:

Cov.:

AF XY:

0.0000805

AC XY:

AN XY:

74514

show subpopulations

Gnomad4 AFR

AF:

0.000361

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:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.000110

ESP6500AA

AF:

0.000455

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000332

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Dec 14, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2582C>G (p.S861C) alteration is located in exon 16 (coding exon 15) of the MED16 gene. This alteration results from a C to G substitution at nucleotide position 2582, causing the serine (S) at amino acid position 861 to be replaced by a cysteine (C). 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

0.068

BayesDel_addAF

Benign

-0.46

BayesDel_noAF

Benign

-0.60

CADD

Benign

8.1

DANN

Benign

0.82

DEOGEN2

Benign

0.029

T;T;.

Eigen

Benign

-1.1

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.18

LIST_S2

Benign

0.31

.;T;T

M_CAP

Benign

0.016

MetaRNN

Benign

0.037

T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.0

N;N;.

PrimateAI

Benign

0.28

PROVEAN

Benign

-0.060

.;N;.

REVEL

Benign

0.067

Sift

Uncertain

0.013

.;D;.

Sift4G

Uncertain

0.014

D;D;T

Polyphen

0.022

B;B;.

Vest4

0.13

MVP

0.10

ClinPred

0.013

GERP RS

0.84

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.063

gMVP

0.29

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over