14-70584841-G-C

Position:

• chr14-70584841-G-C

Variant summary

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

The NM_005466.4(MED6):​c.713C>G​(p.Pro238Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,678 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: MED6 NM_005466.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.49

Genes affected

MED6 (HGNC:19970): (mediator complex subunit 6) Enables transcription coactivator activity. Acts upstream of or within positive regulation of transcription by RNA polymerase II. Located in nucleoplasm. Part of mediator complex. [provided by Alliance of Genome Resources, Apr 2022]

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/exons	MANE	UniProt
MED6	NM_005466.4	c.713C>G	p.Pro238Arg	missense_variant	8/8	ENST00000256379.10
MED6	NM_001284211.2	c.713C>G	p.Pro238Arg	missense_variant	8/9
MED6	NM_001284209.2	c.734C>G	p.Pro245Arg	missense_variant	8/8
MED6	NM_001284210.2	c.*51C>G		3_prime_UTR_variant	7/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MED6	ENST00000256379.10	c.713C>G	p.Pro238Arg	missense_variant	8/8	1	NM_005466.4	P4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461678 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 727132

Gnomad4 AFR exome AF: 0.00

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: 0.0000166

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

May 16, 2024

The c.713C>G (p.P238R) alteration is located in exon 8 (coding exon 8) of the MED6 gene. This alteration results from a C to G substitution at nucleotide position 713, causing the proline (P) at amino acid position 238 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	Uncertain	0.36
BayesDel_addAF	Pathogenic	0.25	D
BayesDel_noAF	Uncertain	0.12
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.26	.;.;T;.
Eigen	Pathogenic	0.81
Eigen_PC	Pathogenic	0.81
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.92	D;D;D;D
M_CAP	Benign	0.016	T
MetaRNN	Uncertain	0.67	D;D;D;D
MetaSVM	Uncertain	0.073	D
MutationAssessor	Uncertain	2.7	.;.;M;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.57	T
PROVEAN	Pathogenic	-5.2	D;.;D;D
REVEL	Uncertain	0.37
Sift	Uncertain	0.0040	D;.;D;D
Sift4G	Uncertain	0.0020	D;D;D;D
Polyphen		1.0	.;.;D;.
Vest4		0.78
MutPred		0.34		Loss of glycosylation at P238 (P = 0.0119);Loss of glycosylation at P238 (P = 0.0119);Loss of glycosylation at P238 (P = 0.0119);.;
MVP		0.89
MPC		0.91
ClinPred		0.98	D
GERP RS		5.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.50
gMVP		0.43

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: chr14-71051558;