11-92981915-G-A

Variant names:

• chr11-92981915-G-A
• rs8192553
• NM_005959.5:c.692G>A

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_005959.5(MTNR1B):​c.692G>A​(p.Arg231His) variant causes a missense change. The variant allele was found at a frequency of 0.00613 in 1,614,166 control chromosomes in the GnomAD database, including 35 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R231S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0039 (2 hom., cov: 33)
  • Exomes 𝑓: 0.0064 (33 hom.)
• Consequence: MTNR1B NM_005959.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.63
• Publications: 15 publications found

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]

ACMG classification

Our verdict: Benign. The variant received -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.010777742).
• BS2: High Homozygotes in GnomAd4 at 2 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005959.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MTNR1B	NM_005959.5	MANE Select	c.692G>A	p.Arg231His	missense	Exon 2 of 2	NP_005950.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MTNR1B	ENST00000257068.3	TSL:1 MANE Select	c.692G>A	p.Arg231His	missense	Exon 2 of 2	ENSP00000257068.2
	MTNR1B	ENST00000532482.1	TSL:5	n.*583G>A		non_coding_transcript_exon	Exon 3 of 3	ENSP00000436101.1
	MTNR1B	ENST00000532482.1	TSL:5	n.*583G>A		3_prime_UTR	Exon 3 of 3	ENSP00000436101.1

Frequencies

GnomAD3 genomes AF: 0.00390 AC: 594 AN: 152208 Hom.: 2 Cov.: 33

Gnomad AFR AF: 0.00118

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00170

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00555

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00667

Gnomad OTH AF: 0.00191

GnomAD2 exomes AF: 0.00393 AC: 988 AN: 251336 AF XY: 0.00406

Gnomad AFR exome AF: 0.00111

Gnomad AMR exome AF: 0.00150

Gnomad ASJ exome AF: 0.000595

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00565

Gnomad NFE exome AF: 0.00662

Gnomad OTH exome AF: 0.00245

GnomAD4 exome AF: 0.00636 AC: 9293 AN: 1461840 Hom.: 33 Cov.: 31 AF XY: 0.00617 AC XY: 4488 AN XY: 727226

African (AFR) AF: 0.000687 AC: 23 AN: 33480

American (AMR) AF: 0.00174 AC: 78 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.000612 AC: 16 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.000788 AC: 68 AN: 86258

European-Finnish (FIN) AF: 0.00465 AC: 248 AN: 53372

Middle Eastern (MID) AF: 0.000693 AC: 4 AN: 5768

European-Non Finnish (NFE) AF: 0.00770 AC: 8568 AN: 1112006

Other (OTH) AF: 0.00477 AC: 288 AN: 60396

GnomAD4 genome AF: 0.00391 AC: 595 AN: 152326 Hom.: 2 Cov.: 33 AF XY: 0.00372 AC XY: 277 AN XY: 74486

African (AFR) AF: 0.00118 AC: 49 AN: 41566

American (AMR) AF: 0.00170 AC: 26 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.000415 AC: 2 AN: 4824

European-Finnish (FIN) AF: 0.00555 AC: 59 AN: 10626

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00669 AC: 455 AN: 68036

Other (OTH) AF: 0.00189 AC: 4 AN: 2112

Alfa AF: 0.00556 Hom.: 19

Bravo AF: 0.00385

TwinsUK AF: 0.00863 AC: 32

ALSPAC AF: 0.00727 AC: 28

ESP6500AA AF: 0.00182 AC: 8

ESP6500EA AF: 0.00663 AC: 57

ExAC AF: 0.00385 AC: 467

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00731

EpiControl AF: 0.00735

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.50	T
BayesDel_noAF	Benign	-0.48
CADD	Benign	17
DANN	Uncertain	1.0
DEOGEN2	Benign	0.39	T
Eigen	Benign	-0.066
Eigen_PC	Benign	-0.11
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Uncertain	0.87	D
M_CAP	Benign	0.0068	T
MetaRNN	Benign	0.011	T
MetaSVM	Benign	-0.94	T
MutationAssessor	Uncertain	2.4	M
PhyloP100		3.6
PrimateAI	Benign	0.31	T
PROVEAN	Uncertain	-4.2	D
REVEL	Benign	0.12
Sift	Uncertain	0.015	D
Sift4G	Uncertain	0.0020	D
Polyphen		0.27	B
Vest4		0.14
MVP		0.63
MPC		0.24
ClinPred		0.053	T
GERP RS		0.29
Varity_R		0.18
gMVP		0.45
Mutation Taster		=92/8	polymorphism

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

Other links and lift over

dbSNP: rs8192553; hg19: chr11-92715081; COSMIC: COSV57068202;