11-64804661-C-G

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 1P and 6B. PP2BP4BP6BS2

The NM_001370259.2(MEN1):ā€‹c.1506G>Cā€‹(p.Lys502Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000144 in 1,599,226 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: š‘“ 0.00011 ( 0 hom., cov: 33)
Exomes š‘“: 0.0000041 ( 0 hom. )

Consequence

MEN1
NM_001370259.2 missense

Scores

2
5
12

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:3

Conservation

PhyloP100: 0.508
Variant links:
Genes affected
MEN1 (HGNC:7010): (menin 1) This gene encodes menin, a tumor suppressor associated with a syndrome known as multiple endocrine neoplasia type 1. Menin is a scaffold protein that functions in histone modification and epigenetic gene regulation. It is thought to regulate several pathways and processes by altering chromatin structure through the modification of histones. [provided by RefSeq, May 2019]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -5 ACMG points.

PP2
Missense variant in the MEN1 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 113 curated pathogenic missense variants (we use a threshold of 10). The gene has 20 curated benign missense variants. Trascript score misZ: 4.1921 (above the threshold of 3.09). GenCC associations: The gene is linked to multiple endocrine neoplasia type 1, pituitary gigantism, familial isolated hyperparathyroidism.
BP4
Computational evidence support a benign effect (MetaRNN=0.26863402).
BP6
Variant 11-64804661-C-G is Benign according to our data. Variant chr11-64804661-C-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 403821.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=3, Benign=2, Likely_benign=1}.
BS2
High AC in GnomAd4 at 17 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
MEN1NM_001370259.2 linkc.1506G>C p.Lys502Asn missense_variant Exon 10 of 10 ENST00000450708.7 NP_001357188.2

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
MEN1ENST00000450708.7 linkc.1506G>C p.Lys502Asn missense_variant Exon 10 of 10 5 NM_001370259.2 ENSP00000394933.3 O00255-2

Frequencies

GnomAD3 genomes
AF:
0.000112
AC:
17
AN:
152202
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.000410
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:
0.00
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000136
AC:
3
AN:
221350
Hom.:
0
AF XY:
0.00
AC XY:
0
AN XY:
122352
show subpopulations
Gnomad AFR exome
AF:
0.000230
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:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000415
AC:
6
AN:
1447024
Hom.:
0
Cov.:
42
AF XY:
0.00000278
AC XY:
2
AN XY:
719648
show subpopulations
Gnomad4 AFR exome
AF:
0.000151
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:
0.00
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.0000167
GnomAD4 genome
AF:
0.000112
AC:
17
AN:
152202
Hom.:
0
Cov.:
33
AF XY:
0.0000941
AC XY:
7
AN XY:
74356
show subpopulations
Gnomad4 AFR
AF:
0.000410
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:
0.00
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000712
Hom.:
0
Bravo
AF:
0.000132
ExAC
AF:
0.0000167
AC:
2

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:3Benign:3
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

Hereditary cancer-predisposing syndrome Uncertain:1Benign:1
Benign, criteria provided, single submitterclinical testingAmbry GeneticsJan 25, 2022This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -
Uncertain significance, criteria provided, single submittercurationSema4, Sema4Jan 01, 2022- -
Multiple endocrine neoplasia, type 1 Benign:2
Benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpFeb 02, 2025- -
Likely benign, criteria provided, single submitterclinical testingMyriad Genetics, Inc.Aug 06, 2024This variant is considered likely benign. This variant has been observed at a population frequency that is significantly greater than expected given the associated disease prevalence and penetrance. -
not provided Uncertain:1
Uncertain significance, criteria provided, single submitternot providedBreakthrough Genomics, Breakthrough Genomics-- -
MEN1-related disorder Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingPreventionGenetics, part of Exact SciencesSep 22, 2022The MEN1 c.1521G>C variant is predicted to result in the amino acid substitution p.Lys507Asn. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.032% of alleles in individuals of African descent in gnomAD (http://gnomad.broadinstitute.org/variant/11-64572133-C-G) and is interpreted as a variant of uncertain significance in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/403821/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
0.41
BayesDel_addAF
Benign
-0.0025
T
BayesDel_noAF
Benign
-0.24
CADD
Benign
19
DANN
Uncertain
1.0
DEOGEN2
Benign
0.27
T;.;.;.;.;T;T;T;T
Eigen
Benign
-0.37
Eigen_PC
Benign
-0.27
FATHMM_MKL
Uncertain
0.84
D
LIST_S2
Benign
0.83
T;T;.;.;T;.;.;T;.
M_CAP
Pathogenic
0.75
D
MetaRNN
Benign
0.27
T;T;T;T;T;T;T;T;T
MetaSVM
Uncertain
0.73
D
MutationAssessor
Benign
0.90
.;.;.;.;.;L;L;L;L
PrimateAI
Pathogenic
0.87
D
PROVEAN
Benign
-1.0
N;N;N;N;N;N;N;N;N
REVEL
Uncertain
0.31
Sift
Benign
0.031
D;T;T;T;T;D;D;D;D
Sift4G
Benign
0.21
T;T;T;T;T;T;T;T;T
Polyphen
0.30, 0.35
.;B;B;B;B;B;B;B;B
Vest4
0.25
MutPred
0.36
.;.;.;.;.;Loss of methylation at K507 (P = 0.0021);Loss of methylation at K507 (P = 0.0021);Loss of methylation at K507 (P = 0.0021);Loss of methylation at K507 (P = 0.0021);
MVP
0.76
MPC
1.7
ClinPred
0.10
T
GERP RS
2.6
Varity_R
0.095
gMVP
0.82

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: rs774296730; hg19: chr11-64572133; API