Genetic Variant MC2R:c.-129+574C>T (chr18-13914914-G-A) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_000529.2(MC2R):c.-129+574C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.409 in 152,126 control chromosomes in the GnomAD database, including 13,600 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.41 ( 13600 hom., cov: 33)

Consequence

MC2R
NM_000529.2 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -1.26

Publications

5 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:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.92).

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.561 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein	UniProt
MC2R	NM_000529.2 link	c.-129+574C>T	intron_variant	Intron 1 of 1	ENST00000327606.4	NP_000520.1	Q01718
MC2R	NM_001291911.1 link	c.-129+716C>T	intron_variant	Intron 1 of 1		NP_001278840.1	Q01718
MC2R	XM_017025781.2 link	c.-661+574C>T	intron_variant	Intron 1 of 2		XP_016881270.1	Q01718
MC2R	XM_047437537.1 link	c.-818+574C>T	intron_variant	Intron 1 of 3		XP_047293493.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MC2R	ENST00000327606.4 link	c.-129+574C>T		intron_variant	Intron 1 of 1	1	NM_000529.2	ENSP00000333821.2		Q01718
MC2R	ENST00000399821.2 link	c.-129+716C>T		intron_variant	Intron 1 of 1	3		ENSP00000382718.2		R4GMM0

Frequencies

GnomAD3 genomes

AF:

0.409

AC:

62157

AN:

152008

Hom.:

13579

Cov.:

show subpopulations

Gnomad AFR

AF:

0.567

Gnomad AMI

AF:

0.329

Gnomad AMR

AF:

0.355

Gnomad ASJ

AF:

0.379

Gnomad EAS

AF:

0.208

Gnomad SAS

AF:

0.202

Gnomad FIN

AF:

0.384

Gnomad MID

AF:

0.472

Gnomad NFE

AF:

0.362

Gnomad OTH

AF:

0.394

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome

AF:

0.409

AC:

62217

AN:

152126

Hom.:

13600

Cov.:

AF XY:

0.407

AC XY:

30288

AN XY:

74368

show subpopulations

African (AFR)

AF:

0.567

AC:

23521

AN:

41488

American (AMR)

AF:

0.355

AC:

5430

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.379

AC:

1317

AN:

3472

East Asian (EAS)

AF:

0.208

AC:

1079

AN:

5180

South Asian (SAS)

AF:

0.203

AC:

978

AN:

4824

European-Finnish (FIN)

AF:

0.384

AC:

4057

AN:

10564

Middle Eastern (MID)

AF:

0.459

AC:

135

AN:

294

European-Non Finnish (NFE)

AF:

0.362

AC:

24581

AN:

67986

Other (OTH)

AF:

0.388

AC:

819

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

1844

3688

5532

7376

9220

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

558

1116

1674

2232

2790

<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:

0.376

Hom.:

14435

Bravo

AF:

0.417

Asia WGS

AF:

0.239

AC:

835

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.92

CADD

Benign

0.13

(source)

DANN

Benign

0.73

PhyloP100

-1.3

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over