Genetic Variant MIDN:p.Val231Leu (chr19-1254344-G-C) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_001388306.1(MIDN):c.691G>C(p.Val231Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000409 in 1,565,492 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000046 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000040 ( 0 hom. )

Consequence

MIDN
NM_001388306.1 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.89

Variant links:

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]

MIDN links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.06646481).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MIDN	NM_001388306.1 link	c.691G>C	p.Val231Leu	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 link	c.691G>C	p.Val231Leu	missense_variant	Exon 6 of 9		NM_001388306.1	ENSP00000507955.1		A0A804HKJ8

Frequencies

GnomAD3 genomes

AF:

0.0000460

AC:

AN:

152178

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

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:

0.0000882

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000581

AC:

AN:

172094

Hom.:

AF XY:

0.00

AC XY:

AN XY:

95206

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:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000137

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000403

AC:

AN:

1413196

Hom.:

Cov.:

AF XY:

0.0000414

AC XY:

AN XY:

700798

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:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000521

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000460

AC:

AN:

152296

Hom.:

Cov.:

AF XY:

0.0000403

AC XY:

AN XY:

74466

show subpopulations

Gnomad4 AFR

AF:

0.0000240

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:

0.0000883

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000264

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Nov 08, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.562G>C (p.V188L) alteration is located in exon 5 (coding exon 4) of the MIDN gene. This alteration results from a G to C substitution at nucleotide position 562, causing the valine (V) at amino acid position 188 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

0.096

BayesDel_addAF

Benign

-0.26

BayesDel_noAF

Benign

-0.61

CADD

Benign

7.0

DANN

Benign

0.94

DEOGEN2

Benign

0.096

.;T;T

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.34

LIST_S2

Benign

0.74

T;T;.

M_CAP

Benign

0.047

MetaRNN

Benign

0.066

T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.3

.;L;L

PrimateAI

Pathogenic

0.85

PROVEAN

Benign

-0.90

.;N;.

REVEL

Benign

0.036

Sift

Benign

0.18

.;T;.

Sift4G

Benign

0.67

T;T;T

Polyphen

0.0090

.;B;B

Vest4

0.22, 0.21

MutPred

0.096

Loss of glycosylation at S189 (P = 0.1136);Loss of glycosylation at S189 (P = 0.1136);Loss of glycosylation at S189 (P = 0.1136);

MVP

0.13

MPC

0.33

ClinPred

0.031

GERP RS

1.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.3

Varity_R

0.12

gMVP

0.14

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