rs2186944

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001291911.1(MC2R):c.-129+87C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0444 in 153,078 control chromosomes in the GnomAD database, including 341 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.045 ( 339 hom., cov: 33)

Exomes 𝑓: 0.017 ( 2 hom. )

Consequence

MC2R
NM_001291911.1 intron

Scores

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 0.379

Publications

10 publications found

Variant links:

Genes affected

MC2R (HGNC:6930): (melanocortin 2 receptor) MC2R encodes one member of the five-member G-protein associated melanocortin receptor family. Melanocortins (melanocyte-stimulating hormones and adrenocorticotropic hormone) are peptides derived from pro-opiomelanocortin (POMC). MC2R is selectively activated by adrenocorticotropic hormone, whereas the other four melanocortin receptors recognize a variety of melanocortin ligands. Mutations in MC2R can result in familial glucocorticoid deficiency. Alternate transcript variants have been found for this gene. [provided by RefSeq, May 2014]

MC2R Gene-Disease associations (from GenCC):

glucocorticoid deficiency 1
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)
familial glucocorticoid deficiency
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

MC2R links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.88).

BP6

Variant 18-13915543-G-A is Benign according to our data. Variant chr18-13915543-G-A is described in CliVar as Likely_benign. Clinvar id is 369250.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr18-13915543-G-A is described in CliVar as Likely_benign. Clinvar id is 369250.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr18-13915543-G-A is described in CliVar as Likely_benign. Clinvar id is 369250.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr18-13915543-G-A is described in CliVar as Likely_benign. Clinvar id is 369250.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.171 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein	UniProt
MC2R	NM_001291911.1 link	c.-129+87C>T	intron_variant	Intron 1 of 1		NP_001278840.1	Q01718
MC2R	NM_000529.2 link	c.-184C>T	upstream_gene_variant		ENST00000327606.4	NP_000520.1	Q01718
MC2R	XM_017025781.2 link	c.-716C>T	upstream_gene_variant			XP_016881270.1	Q01718
MC2R	XM_047437537.1 link	c.-873C>T	upstream_gene_variant			XP_047293493.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MC2R	ENST00000399821.2 link	c.-129+87C>T		intron_variant	Intron 1 of 1	3		ENSP00000382718.2		R4GMM0
MC2R	ENST00000327606.4 link	c.-184C>T		upstream_gene_variant		1	NM_000529.2	ENSP00000333821.2		Q01718

Frequencies

GnomAD3 genomes

AF:

0.0445

AC:

6772

AN:

152132

Hom.:

337

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0983

Gnomad AMI

AF:

0.0505

Gnomad AMR

AF:

0.0683

Gnomad ASJ

AF:

0.0153

Gnomad EAS

AF:

0.180

Gnomad SAS

AF:

0.0313

Gnomad FIN

AF:

0.00575

Gnomad MID

AF:

0.0380

Gnomad NFE

AF:

0.00470

Gnomad OTH

AF:

0.0373

GnomAD4 exome

AF:

0.0169

AC:

AN:

828

Hom.:

Cov.:

AF XY:

0.0106

AC XY:

AN XY:

470

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

American (AMR)

AF:

0.167

AC:

AN:

Ashkenazi Jewish (ASJ)

AF:

0.0556

AC:

AN:

East Asian (EAS)

AF:

0.263

AC:

AN:

South Asian (SAS)

AC:

AN:

European-Finnish (FIN)

AF:

0.00

AC:

AN:

472

Middle Eastern (MID)

AC:

AN:

European-Non Finnish (NFE)

AF:

0.00391

AC:

AN:

256

Other (OTH)

AF:

0.0294

AC:

AN:

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0446

AC:

6786

AN:

152250

Hom.:

339

Cov.:

AF XY:

0.0460

AC XY:

3423

AN XY:

74432

show subpopulations

African (AFR)

AF:

0.0982

AC:

4079

AN:

41532

American (AMR)

AF:

0.0682

AC:

1043

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.0153

AC:

AN:

3470

East Asian (EAS)

AF:

0.180

AC:

936

AN:

5186

South Asian (SAS)

AF:

0.0319

AC:

154

AN:

4828

European-Finnish (FIN)

AF:

0.00575

AC:

AN:

10614

Middle Eastern (MID)

AF:

0.0442

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00470

AC:

320

AN:

68018

Other (OTH)

AF:

0.0384

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

322

644

966

1288

1610

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

152

228

304

380

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0331

Hom.:

Bravo

AF:

0.0522

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Glucocorticoid Deficiency

Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.88

CADD

Benign

(source)

DANN

Benign

0.93

PhyloP100

0.38

PromoterAI

-0.019

Neutral

(source)

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over