19-1251878-C-G

Variant names:

• chr19-1251878-C-G
• rs757558824
• NM_001388306.1:c.361C>G

Variant summary

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

The NM_001388306.1(MIDN):​c.361C>G​(p.Leu121Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,128 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: 34)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: MIDN NM_001388306.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.378

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=0.25828677).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MIDN	NM_001388306.1	c.361C>G	p.Leu121Val	missense_variant	Exon 4 of 9	ENST00000682408.1	NP_001375235.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MIDN	ENST00000682408.1	c.361C>G	p.Leu121Val	missense_variant	Exon 4 of 9		NM_001388306.1	ENSP00000507955.1
MIDN	ENST00000591446.7	c.361C>G	p.Leu121Val	missense_variant	Exon 3 of 7	1		ENSP00000467679.1
MIDN	ENST00000300952.7	c.361C>G	p.Leu121Val	missense_variant	Exon 4 of 8	5		ENSP00000300952.2
MIDN	ENST00000591302.1	n.429C>G		non_coding_transcript_exon_variant	Exon 2 of 3	2

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461128 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 726834

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: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 34

ExAC AF: 0.00000825 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Oct 01, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.361C>G (p.L121V) alteration is located in exon 4 (coding exon 3) of the MIDN gene. This alteration results from a C to G substitution at nucleotide position 361, causing the leucine (L) at amino acid position 121 to be replaced by a valine (V). 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	0.98
BayesDel_addAF	Benign	-0.036	T
BayesDel_noAF	Benign	-0.29
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.47	.;T;T
Eigen	Benign	0.15
Eigen_PC	Benign	0.028
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Uncertain	0.97	D;D;.
M_CAP	Uncertain	0.094	D
MetaRNN	Benign	0.26	T;T;T
MetaSVM	Benign	-0.62	T
MutationAssessor	Benign	1.8	.;L;L
PrimateAI	Pathogenic	0.88	D
PROVEAN	Benign	-2.0	.;N;.
REVEL	Benign	0.12
Sift	Uncertain	0.0040	.;D;.
Sift4G	Uncertain	0.021	D;D;D
Polyphen		0.99	.;D;D
Vest4		0.66, 0.66
MutPred		0.12		Loss of solvent accessibility (P = 0.0533);Loss of solvent accessibility (P = 0.0533);Loss of solvent accessibility (P = 0.0533);
MVP		0.43
MPC		0.64
ClinPred		0.93	D
GERP RS		2.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.20
gMVP		0.48

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: rs757558824; hg19: chr19-1251877;