chr11-92981769-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_005959.5(MTNR1B):​c.546G>T​(p.Glu182Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000129 in 1,614,098 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000072 ( 0 hom., cov: 33)
Exomes 𝑓: 0.00014 ( 0 hom. )

Consequence

MTNR1B
NM_005959.5 missense

Scores

4
15

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.217
Variant links:
Genes affected
MTNR1B (HGNC:7464): (melatonin receptor 1B) This gene encodes one of two high affinity forms of a receptor for melatonin, the primary hormone secreted by the pineal gland. This gene product is an integral membrane protein that is a G-protein coupled, 7-transmembrane receptor. It is found primarily in the retina and brain although this detection requires RT-PCR. It is thought to participate in light-dependent functions in the retina and may be involved in the neurobiological effects of melatonin. [provided by RefSeq, Jul 2008]

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ACMG classification

Classification made for transcript

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=0.18916851).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
MTNR1BNM_005959.5 linkuse as main transcriptc.546G>T p.Glu182Asp missense_variant 2/2 ENST00000257068.3 NP_005950.1
MTNR1BXM_011542839.3 linkuse as main transcriptc.546G>T p.Glu182Asp missense_variant 2/3 XP_011541141.1
MTNR1BXM_017017777.2 linkuse as main transcriptc.420G>T p.Glu140Asp missense_variant 2/3 XP_016873266.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
MTNR1BENST00000257068.3 linkuse as main transcriptc.546G>T p.Glu182Asp missense_variant 2/21 NM_005959.5 ENSP00000257068 P1
MTNR1BENST00000528076.1 linkuse as main transcriptc.166-3038G>T intron_variant 3 ENSP00000433573
MTNR1BENST00000532482.1 linkuse as main transcriptc.*437G>T 3_prime_UTR_variant, NMD_transcript_variant 3/35 ENSP00000436101

Frequencies

GnomAD3 genomes
AF:
0.0000723
AC:
11
AN:
152206
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.0000482
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:
0.000132
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000875
AC:
22
AN:
251400
Hom.:
0
AF XY:
0.0000736
AC XY:
10
AN XY:
135864
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:
0.0000462
Gnomad NFE exome
AF:
0.000176
Gnomad OTH exome
AF:
0.000163
GnomAD4 exome
AF:
0.000135
AC:
198
AN:
1461892
Hom.:
0
Cov.:
31
AF XY:
0.000116
AC XY:
84
AN XY:
727248
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:
0.0000187
Gnomad4 NFE exome
AF:
0.000174
Gnomad4 OTH exome
AF:
0.0000497
GnomAD4 genome
AF:
0.0000723
AC:
11
AN:
152206
Hom.:
0
Cov.:
33
AF XY:
0.0000538
AC XY:
4
AN XY:
74354
show subpopulations
Gnomad4 AFR
AF:
0.0000482
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:
0.000132
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000966
Hom.:
0
Bravo
AF:
0.0000793
TwinsUK
AF:
0.00
AC:
0
ALSPAC
AF:
0.000259
AC:
1
ESP6500AA
AF:
0.00
AC:
0
ESP6500EA
AF:
0.000116
AC:
1
ExAC
AF:
0.000123
AC:
15
EpiCase
AF:
0.000109
EpiControl
AF:
0.000415

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsMar 06, 2023The c.546G>T (p.E182D) alteration is located in exon 2 (coding exon 2) of the MTNR1B gene. This alteration results from a G to T substitution at nucleotide position 546, causing the glutamic acid (E) at amino acid position 182 to be replaced by an aspartic acid (D). 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
0.23
BayesDel_addAF
Benign
-0.44
T
BayesDel_noAF
Benign
-0.60
CADD
Benign
17
DANN
Uncertain
1.0
DEOGEN2
Benign
0.18
T
Eigen
Benign
-0.39
Eigen_PC
Benign
-0.50
FATHMM_MKL
Benign
0.61
D
LIST_S2
Uncertain
0.95
D
M_CAP
Benign
0.0029
T
MetaRNN
Benign
0.19
T
MetaSVM
Benign
-0.96
T
MutationAssessor
Benign
1.8
L
MutationTaster
Benign
1.0
N
PrimateAI
Benign
0.37
T
PROVEAN
Benign
-2.2
N
REVEL
Benign
0.071
Sift
Uncertain
0.0030
D
Sift4G
Uncertain
0.0050
D
Polyphen
0.58
P
Vest4
0.053
MutPred
0.44
Gain of loop (P = 0.1069);
MVP
0.42
MPC
0.15
ClinPred
0.12
T
GERP RS
-4.1
Varity_R
0.29
gMVP
0.18

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.

Other links and lift over

dbSNP: rs372043726; hg19: chr11-92714935; API