X-107927009-G-C

Variant names:

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

Variant summary

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

The NM_012216.4(MID2):​c.2144G>C​(p.Arg715Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000912 in 1,097,071 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a benign outcome for this variant. 16/21 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 variant affecting the same amino acid position, but resulting in a different missense (i.e. R715L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 9.1e-7 (0 hom. 0 hem.)
• Consequence: MID2 NM_012216.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.19
• Publications: 0 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: 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=0.09158856).

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>C	p.Arg715Pro	missense	Exon 10 of 10	NP_036348.2	Q9UJV3-1
	MID2	NM_001382751.1		c.2084G>C	p.Arg695Pro	missense	Exon 10 of 10	NP_001369680.1
	MID2	NM_052817.3		c.2054G>C	p.Arg685Pro	missense	Exon 10 of 10	NP_438112.2	Q9UJV3-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MID2	ENST00000262843.11	TSL:1 MANE Select	c.2144G>C	p.Arg715Pro	missense	Exon 10 of 10	ENSP00000262843.6	Q9UJV3-1
	MID2	ENST00000443968.2	TSL:1	c.2054G>C	p.Arg685Pro	missense	Exon 10 of 10	ENSP00000413976.2	Q9UJV3-2
	MID2	ENST00000921443.1		c.2048G>C	p.Arg683Pro	missense	Exon 9 of 9	ENSP00000591502.1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome AF: 9.12e-7 AC: 1 AN: 1097071 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 362601

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 26371

American (AMR) AF: 0.00 AC: 0 AN: 35132

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

East Asian (EAS) AF: 0.00 AC: 0 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: 0.00000119 AC: 1 AN: 841297

Other (OTH) AF: 0.00 AC: 0 AN: 46054

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 23

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.46
CADD	Benign	22
DANN	Benign	0.97
DEOGEN2	Benign	0.034	T
FATHMM_MKL	Benign	0.74	D
LIST_S2	Uncertain	0.90	D
M_CAP	Benign	0.013	T
MetaRNN	Benign	0.092	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.0	N
PhyloP100		1.2
PrimateAI	Benign	0.48	T
PROVEAN	Benign	-0.50	N
REVEL	Benign	0.088
Sift	Benign	0.12	T
Sift4G	Benign	0.28	T
Polyphen		0.0	B
Vest4		0.36
MutPred		0.40		Gain of disorder (P = 0.0885)
MVP		0.44
MPC		0.65
ClinPred		0.53	D
GERP RS		4.4
Varity_R		0.23
gMVP		0.65
Mutation Taster		=57/43	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;