X-107841332-C-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BS2

The NM_012216.4(MID2):c.667C>T(p.Arg223Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000902 in 110,830 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0000090 (0 hom., 1 hem., cov: 23)
  • Exomes 𝑓: 0.0000046 (0 hom. 5 hem.)
  • Failed GnomAD Quality Control
• Consequence: MID2 NM_012216.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.80

Genes affected

MID2 (HGNC:7096): (midline 2) The protein encoded by this gene is a member of the tripartite motif (TRIM) family. The TRIM motif includes three zinc-binding domains, a RING, a B-box type 1 and a B-box type 2, and a coiled-coil region. The protein localizes to microtubular structures in the cytoplasm. Alternate splicing of this gene results in two transcript variants encoding different isoforms. [provided by RefSeq, Feb 2009]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BS2: High Hemizygotes in GnomAdExome at 2 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MID2	NM_012216.4	c.667C>T	p.Arg223Cys	missense_variant	2/10	ENST00000262843.11
MID2	NM_001382751.1	c.607C>T	p.Arg203Cys	missense_variant	2/10
MID2	NM_052817.3	c.667C>T	p.Arg223Cys	missense_variant	2/10
MID2	NM_001382752.1	c.607C>T	p.Arg203Cys	missense_variant	2/10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MID2	ENST00000262843.11	c.667C>T	p.Arg223Cys	missense_variant	2/10	1	NM_012216.4
MID2	ENST00000443968.2	c.667C>T	p.Arg223Cys	missense_variant	2/10	1		P1
MID2	ENST00000451923.1	c.607C>T	p.Arg203Cys	missense_variant	2/2	3

Frequencies

GnomAD3 genomes AF: 0.00000902 AC: 1 AN: 110830 Hom.: 0 Cov.: 23 AF XY: 0.0000302 AC XY: 1 AN XY: 33098

Gnomad AFR AF: 0.00

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: 0.0000189

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000167 AC: 3 AN: 179434 Hom.: 0 AF XY: 0.0000311 AC XY: 2 AN XY: 64402

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000546

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000125

Gnomad OTH exome AF: 0.000226

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000457 AC: 5 AN: 1095015 Hom.: 0 Cov.: 31 AF XY: 0.0000139 AC XY: 5 AN XY: 360609

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: 0.0000373

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000357

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.00000902 AC: 1 AN: 110830 Hom.: 0 Cov.: 23 AF XY: 0.0000302 AC XY: 1 AN XY: 33098

Gnomad4 AFR AF: 0.00

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: 0.0000189

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000108 Hom.: 1

Bravo AF: 0.00000378

ExAC AF: 0.0000412 AC: 5

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Dec 01, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.46
BayesDel_addAF	Benign	0.0032	T
BayesDel_noAF	Uncertain	-0.020
Cadd	Uncertain	25
Dann	Pathogenic	1.0
DEOGEN2	Benign	0.036	T;T;.
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.97	D;D;D
M_CAP	Pathogenic	0.72	D
MetaRNN	Uncertain	0.66	D;D;D
MetaSVM	Benign	-0.39	T
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.87	D
PROVEAN	Pathogenic	-4.5	D;D;D
REVEL	Uncertain	0.36
Sift	Uncertain	0.0030	D;D;D
Sift4G	Uncertain	0.0020	D;D;D
Polyphen		1.0	.;D;D
Vest4		0.25, 0.51
MutPred		0.61		.;Gain of ubiquitination at K219 (P = 0.0467);Gain of ubiquitination at K219 (P = 0.0467);
MVP		0.55
MPC		1.4
ClinPred		0.80	D
GERP RS		5.9
Varity_R		0.59
gMVP		0.84

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

LitVar

Other links and lift over

dbSNP: rs751834460; hg19: chrX-107084562; COSMIC: COSV53312238;