19-1254317-C-T

Variant names:

• chr19-1254317-C-T
• rs1338724071
• NM_001388306.1:c.664C>T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001388306.1(MIDN):​c.664C>T​(p.Arg222Trp) variant causes a missense change. The variant allele was found at a frequency of 0.00000494 in 1,418,380 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000049 (0 hom.)
• Consequence: MIDN NM_001388306.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.68

Genes affected

MIDN (HGNC:16298): (midnolin) Predicted to enable kinase binding activity. Predicted to be involved in negative regulation of glucokinase activity and negative regulation of insulin secretion. Located in cytoplasm and nucleus. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.24458739).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MIDN	NM_001388306.1	c.664C>T	p.Arg222Trp	missense_variant	Exon 6 of 9	ENST00000682408.1	NP_001375235.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MIDN	ENST00000682408.1	c.664C>T	p.Arg222Trp	missense_variant	Exon 6 of 9		NM_001388306.1	ENSP00000507955.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000494 AC: 7 AN: 1418380 Hom.: 0 Cov.: 34 AF XY: 0.00000568 AC XY: 4 AN XY: 703746

Gnomad4 AFR exome AF: 0.0000310

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000120

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000456

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000756

Asia WGS AF: 0.000289 AC: 1 AN: 3476

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Dec 15, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.535C>T (p.R179W) alteration is located in exon 5 (coding exon 4) of the MIDN gene. This alteration results from a C to T substitution at nucleotide position 535, causing the arginine (R) at amino acid position 179 to be replaced by a tryptophan (W). 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	0.22
BayesDel_addAF	Benign	-0.035	T
BayesDel_noAF	Benign	-0.29
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.26	.;T;T
Eigen	Benign	-0.29
Eigen_PC	Benign	-0.44
FATHMM_MKL	Benign	0.43	N
LIST_S2	Uncertain	0.87	D;T;.
M_CAP	Uncertain	0.10	D
MetaRNN	Benign	0.24	T;T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	1.9	.;M;M
PrimateAI	Pathogenic	0.88	D
PROVEAN	Benign	-2.3	.;N;.
REVEL	Benign	0.12
Sift	Uncertain	0.027	.;D;.
Sift4G	Uncertain	0.047	D;D;D
Polyphen		1.0	.;D;D
Vest4		0.39, 0.39
MutPred		0.26		Gain of catalytic residue at P182 (P = 0.0235);Gain of catalytic residue at P182 (P = 0.0235);Gain of catalytic residue at P182 (P = 0.0235);
MVP		0.34
MPC		0.69
ClinPred		0.82	D
GERP RS		3.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.11
gMVP		0.25

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: rs1338724071; hg19: chr19-1254316;