11-92982146-A-C

Variant names:

• chr11-92982146-A-C
• rs184917682
• NM_005959.5:c.923A>C

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_005959.5(MTNR1B):​c.923A>C​(p.Tyr308Ser) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as risk factor (no stars).

• Frequency: Genomes: not found (cov: 33)
• Consequence: MTNR1B NM_005959.5 missense
• Clinical Significance: risk factor no assertion criteria provided O:1
• Conservation: PhyloP100: 6.84
• Publications: 7 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: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.973

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MTNR1B	NM_005959.5	c.923A>C	p.Tyr308Ser	missense_variant	Exon 2 of 2	ENST00000257068.3	NP_005950.1
MTNR1B	XM_011542839.3	c.923A>C	p.Tyr308Ser	missense_variant	Exon 2 of 3		XP_011541141.1
MTNR1B	XM_017017777.2	c.797A>C	p.Tyr266Ser	missense_variant	Exon 2 of 3		XP_016873266.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MTNR1B	ENST00000257068.3	c.923A>C	p.Tyr308Ser	missense_variant	Exon 2 of 2	1	NM_005959.5	ENSP00000257068.2
MTNR1B	ENST00000532482.1	n.*814A>C		non_coding_transcript_exon_variant	Exon 3 of 3	5		ENSP00000436101.1
MTNR1B	ENST00000532482.1	n.*814A>C		3_prime_UTR_variant	Exon 3 of 3	5		ENSP00000436101.1
MTNR1B	ENST00000528076.1	c.165-2661A>C		intron_variant	Intron 1 of 1	3		ENSP00000433573.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

Alfa AF: 0.00000462 Hom.: 0

ClinVar

Significance: risk factor

Submissions summary: Other:1

Revision: no assertion criteria provided

Submissions by phenotype

Diabetes mellitus type 2, susceptibility to Other:1

Jan 29, 2012

OMIM

Significance: risk factor

Review Status: no assertion criteria provided

Collection Method: literature only

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.86
BayesDel_addAF	Pathogenic	0.49	D
BayesDel_noAF	Pathogenic	0.47
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.72	D
Eigen	Pathogenic	0.69
Eigen_PC	Uncertain	0.50
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Pathogenic	1.0	D
M_CAP	Uncertain	0.11	D
MetaRNN	Pathogenic	0.97	D
MetaSVM	Pathogenic	0.95	D
MutationAssessor	Pathogenic	4.6	H
PhyloP100		6.8
PrimateAI	Uncertain	0.55	T
PROVEAN	Pathogenic	-6.8	D
REVEL	Pathogenic	0.88
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Vest4		0.99
ClinPred		1.0	D
GERP RS		2.9
Varity_R		0.97
gMVP		0.88
Mutation Taster		=16/84	disease causing

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: rs184917682; hg19: chr11-92715312;