chr19-871054-C-G

Variant names:

• chr19-871054-C-G
• NM_005481.3:c.2298G>C
• MED16 p.Gln766His

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_005481.3(MED16):​c.2298G>C​(p.Gln766His) 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. 14/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar.

• Frequency: Genomes: not found (cov: 33)
• Consequence: MED16 NM_005481.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0960
• Publications: 0 publications found

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 Gene-Disease associations (from GenCC):

• complex neurodevelopmental disorder with or without congenital anomalies

  Inheritance: AR Classification: MODERATE Submitted by: Ambry Genetics

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.13898331).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005481.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MED16	NM_005481.3	MANE Select	c.2298G>C	p.Gln766His	missense	Exon 13 of 16	NP_005472.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MED16	ENST00000325464.6	TSL:5 MANE Select	c.2298G>C	p.Gln766His	missense	Exon 13 of 16	ENSP00000325612.1	Q9Y2X0-1
	MED16	ENST00000312090.10	TSL:1	c.2355G>C	p.Gln785His	missense	Exon 14 of 16	ENSP00000308528.4	Q9Y2X0-3
	MED16	ENST00000395808.7	TSL:1	c.2298G>C	p.Gln766His	missense	Exon 13 of 15	ENSP00000379153.1	Q9Y2X0-2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.48
CADD	Benign	19
DANN	Uncertain	0.99
DEOGEN2	Benign	0.052	T
Eigen	Benign	-0.70
Eigen_PC	Benign	-0.62
FATHMM_MKL	Benign	0.74	D
LIST_S2	Benign	0.78	T
M_CAP	Benign	0.028	D
MetaRNN	Benign	0.14	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.4	L
PhyloP100		0.096
PrimateAI	Uncertain	0.62	T
PROVEAN	Benign	-1.1	N
REVEL	Benign	0.062
Sift	Benign	0.041	D
Sift4G	Benign	0.14	T
PromoterAI		-0.046	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.097
gMVP		0.56
Mutation Taster		=92/8	polymorphism

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

hg19: chr19-871054;