19-1250486-C-A

Variant names:

• chr19-1250486-C-A
• rs763117290
• NM_001388306.1:c.190C>A

Variant summary

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

The NM_001388306.1(MIDN):​c.190C>A​(p.Leu64Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000205 in 1,216,702 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000021 (0 hom.)
• Consequence: MIDN NM_001388306.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.22

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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MIDN	NM_001388306.1	c.190C>A	p.Leu64Ile	missense_variant	Exon 2 of 9	ENST00000682408.1	NP_001375235.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MIDN	ENST00000682408.1	c.190C>A	p.Leu64Ile	missense_variant	Exon 2 of 9		NM_001388306.1	ENSP00000507955.1
MIDN	ENST00000591446.7	c.190C>A	p.Leu64Ile	missense_variant	Exon 1 of 7	1		ENSP00000467679.1
MIDN	ENST00000300952.7	c.190C>A	p.Leu64Ile	missense_variant	Exon 2 of 8	5		ENSP00000300952.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.0000205 AC: 25 AN: 1216702 Hom.: 0 Cov.: 30 AF XY: 0.0000166 AC XY: 10 AN XY: 602182

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: 0.0000248

Gnomad4 OTH exome AF: 0.0000218

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Nov 14, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.190C>A (p.L64I) alteration is located in exon 2 (coding exon 1) of the MIDN gene. This alteration results from a C to A substitution at nucleotide position 190, causing the leucine (L) at amino acid position 64 to be replaced by an isoleucine (I). 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	Pathogenic	0.89
BayesDel_addAF	Benign	0.00097	T
BayesDel_noAF	Benign	-0.24
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Benign	0.27	.;T;T
Eigen	Uncertain	0.46
Eigen_PC	Uncertain	0.34
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Uncertain	0.89	D;D;.
M_CAP	Pathogenic	0.99	D
MetaRNN	Uncertain	0.48	T;T;T
MetaSVM	Uncertain	-0.042	T
MutationAssessor	Uncertain	2.1	.;M;M
PrimateAI	Pathogenic	0.95	D
PROVEAN	Benign	-1.4	.;N;.
REVEL	Benign	0.27
Sift	Uncertain	0.027	.;D;.
Sift4G	Uncertain	0.024	D;D;D
Polyphen		1.0	.;D;D
Vest4		0.30, 0.30
MutPred		0.17		Gain of methylation at K65 (P = 0.083);Gain of methylation at K65 (P = 0.083);Gain of methylation at K65 (P = 0.083);
MVP		0.64
MPC		0.85
ClinPred		0.93	D
GERP RS		2.7
Varity_R		0.25
gMVP		0.26

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: rs763117290; hg19: chr19-1250485; COSMIC: COSV99960093; COSMIC: COSV99960093;