X-107841027-G-T

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4BS2

The NM_012216.4(MID2):c.362G>T(p.Arg121Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000256 in 1,209,093 control chromosomes in the GnomAD database, including 1 homozygotes. There are 11 hemizygotes in GnomAD. In-silico tool predicts 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. R121C) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0000090 ( 0 hom., 0 hem., cov: 23)

Exomes 𝑓: 0.000027 ( 1 hom. 11 hem. )

Consequence

MID2
NM_012216.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 8.19

Variant links:

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]

MID2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -5 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.27583808).

BS2

High Hemizygotes in GnomAdExome at 4 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
MID2	NM_012216.4 linkuse as main transcript	c.362G>T	p.Arg121Leu	missense_variant	2/10	ENST00000262843.11
MID2	NM_001382751.1 linkuse as main transcript	c.302G>T	p.Arg101Leu	missense_variant	2/10
MID2	NM_052817.3 linkuse as main transcript	c.362G>T	p.Arg121Leu	missense_variant	2/10
MID2	NM_001382752.1 linkuse as main transcript	c.302G>T	p.Arg101Leu	missense_variant	2/10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MID2	ENST00000262843.11 linkuse as main transcript	c.362G>T	p.Arg121Leu	missense_variant	2/10	1	NM_012216.4		Q9UJV3-1
MID2	ENST00000443968.2 linkuse as main transcript	c.362G>T	p.Arg121Leu	missense_variant	2/10	1		P1	Q9UJV3-2
MID2	ENST00000451923.1 linkuse as main transcript	c.302G>T	p.Arg101Leu	missense_variant	2/2	3

Frequencies

GnomAD3 genomes

AF:

0.00000900

AC:

AN:

111114

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

33328

show subpopulations

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:

0.0000655

AC:

AN:

183108

Hom.:

AF XY:

0.0000592

AC XY:

AN XY:

67580

show subpopulations

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:

0.000525

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000122

Gnomad OTH exome

AF:

0.000221

GnomAD4 exome

AF:

0.0000273

AC:

AN:

1097979

Hom.:

Cov.:

AF XY:

0.0000303

AC XY:

AN XY:

363343

show subpopulations

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:

0.000406

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000594

Gnomad4 OTH exome

AF:

0.0000434

GnomAD4 genome

AF:

0.00000900

AC:

AN:

111114

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

33328

show subpopulations

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

Bravo

AF:

0.00000378

ExAC

AF:

0.0000577

AC:

EpiCase

AF:

0.000109

EpiControl

AF:

0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 12, 2021

The c.362G>T (p.R121L) alteration is located in exon 2 (coding exon 2) of the MID2 gene. This alteration results from a G to T substitution at nucleotide position 362, causing the arginine (R) at amino acid position 121 to be replaced by a leucine (L). 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

0.31

BayesDel_addAF

Benign

-0.24

BayesDel_noAF

Benign

-0.24

Cadd

Uncertain

Dann

Uncertain

1.0

DEOGEN2

Benign

0.054

T;T;.

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.97

D;D;D

M_CAP

Pathogenic

0.76

MetaRNN

Benign

0.28

T;T;T

MetaSVM

Benign

-0.71

MutationTaster

Benign

1.0

D;D

PrimateAI

Uncertain

0.67

PROVEAN

Uncertain

-2.7

D;N;N

REVEL

Benign

0.18

Sift

Benign

0.10

T;D;D

Sift4G

Benign

0.28

T;T;T

Polyphen

0.076, 0.038

.;B;B

Vest4

0.21, 0.39

MutPred

0.26

.;Loss of glycosylation at S120 (P = 0.0873);Loss of glycosylation at S120 (P = 0.0873);

MVP

0.56

MPC

0.63

ClinPred

0.23

GERP RS

5.9

Varity_R

0.43

gMVP

0.51

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

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