rs370198556

Variant names:

• chrX-107927009-G-A
• rs370198556
• NM_012216.4:c.2144G>A

Your query was ambiguous. Multiple possible variants found:

• chrX-107927009-G-A
• chrX-107927009-G-C

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_012216.4(MID2):​c.2144G>A​(p.Arg715Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000043 in 1,208,482 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 8 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 16/21 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. R715L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00014 (0 hom., 2 hem., cov: 23)
  • Exomes 𝑓: 0.000033 (0 hom. 6 hem.)
• Consequence: MID2 NM_012216.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3 B:1
• Conservation: PhyloP100: 1.19
• Publications: 1 publications found

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 Gene-Disease associations (from GenCC):

• non-syndromic X-linked intellectual disability

  Inheritance: XL Classification: SUPPORTIVE Submitted by: Orphanet
• intellectual disability, X-linked 101

  Inheritance: Unknown Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

ENSG00000236064 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.021393985).
• BS2: High Hemizygotes in GnomAd4 at 2 Unknown,XL gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_012216.4. 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
	MID2	NM_012216.4	MANE Select	c.2144G>A	p.Arg715Gln	missense	Exon 10 of 10	NP_036348.2
	MID2	NM_001382751.1		c.2084G>A	p.Arg695Gln	missense	Exon 10 of 10	NP_001369680.1
	MID2	NM_052817.3		c.2054G>A	p.Arg685Gln	missense	Exon 10 of 10	NP_438112.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MID2	ENST00000262843.11	TSL:1 MANE Select	c.2144G>A	p.Arg715Gln	missense	Exon 10 of 10	ENSP00000262843.6
	MID2	ENST00000443968.2	TSL:1	c.2054G>A	p.Arg685Gln	missense	Exon 10 of 10	ENSP00000413976.2
	MID2	ENST00000921443.1		c.2048G>A	p.Arg683Gln	missense	Exon 9 of 9	ENSP00000591502.1

Frequencies

GnomAD3 genomes AF: 0.000144 AC: 16 AN: 111411 Hom.: 0 Cov.: 23

Gnomad AFR AF: 0.000522

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

GnomAD2 exomes AF: 0.0000876 AC: 16 AN: 182685 AF XY: 0.0000743

Gnomad AFR exome AF: 0.000685

Gnomad AMR exome AF: 0.000183

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000722

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000122

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000328 AC: 36 AN: 1097071 Hom.: 0 Cov.: 30 AF XY: 0.0000165 AC XY: 6 AN XY: 362601

African (AFR) AF: 0.000758 AC: 20 AN: 26371

American (AMR) AF: 0.000114 AC: 4 AN: 35132

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19353

East Asian (EAS) AF: 0.0000331 AC: 1 AN: 30192

South Asian (SAS) AF: 0.00 AC: 0 AN: 54035

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40510

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4127

European-Non Finnish (NFE) AF: 0.00000951 AC: 8 AN: 841297

Other (OTH) AF: 0.0000651 AC: 3 AN: 46054

GnomAD4 genome AF: 0.000144 AC: 16 AN: 111411 Hom.: 0 Cov.: 23 AF XY: 0.0000594 AC XY: 2 AN XY: 33653

African (AFR) AF: 0.000522 AC: 16 AN: 30624

American (AMR) AF: 0.00 AC: 0 AN: 10465

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2640

East Asian (EAS) AF: 0.00 AC: 0 AN: 3572

South Asian (SAS) AF: 0.00 AC: 0 AN: 2617

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6004

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 239

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 53066

Other (OTH) AF: 0.00 AC: 0 AN: 1498

Alfa AF: 0.000239 Hom.: 1

Bravo AF: 0.000234

ESP6500AA AF: 0.000261 AC: 1

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.0000741 AC: 9

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	2	-	not specified (2)
-	-	1	MID2-related disorder (1)
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.064
BayesDel_addAF	Benign	-0.52	T
BayesDel_noAF	Benign	-0.60
CADD	Benign	19
DANN	Benign	0.80
DEOGEN2	Benign	0.034	T
FATHMM_MKL	Uncertain	0.76	D
LIST_S2	Uncertain	0.89	D
M_CAP	Benign	0.0068	T
MetaRNN	Benign	0.021	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	-0.55	N
PhyloP100		1.2
PrimateAI	Benign	0.41	T
PROVEAN	Benign	0.53	N
REVEL	Benign	0.057
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0010	B
Vest4		0.12
MVP		0.49
MPC		0.52
ClinPred		0.022	T
GERP RS		4.4
Varity_R		0.092
gMVP		0.37
Mutation Taster		=98/2	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

Other links and lift over

dbSNP: rs370198556; hg19: chrX-107170239; COSMIC: COSV53308760; COSMIC: COSV53308760;