11-64810034-C-G

Variant names:

• chr11-64810034-C-G
• NM_001370259.2:c.76G>C

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2 PM5 PP2

The NM_001370259.2(MEN1):​c.76G>C​(p.Glu26Gln) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. 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. E26K) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 30)
• Consequence: MEN1 NM_001370259.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.13

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr11-64810034-C-T is described in Lovd as [Pathogenic].
• 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MEN1	NM_001370259.2	c.76G>C	p.Glu26Gln	missense_variant	Exon 2 of 10	ENST00000450708.7	NP_001357188.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MEN1	ENST00000450708.7	c.76G>C	p.Glu26Gln	missense_variant	Exon 2 of 10	5	NM_001370259.2	ENSP00000394933.3

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 30

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.83
BayesDel_addAF	Pathogenic	0.23	D
BayesDel_noAF	Uncertain	0.090
CADD	Benign	23
DANN	Benign	0.88
DEOGEN2	Uncertain	0.48	T;.;.;.;.;D;D;D;D;T;.;T;.;.
Eigen	Benign	0.0065
Eigen_PC	Benign	0.14
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.89	D;D;.;.;D;.;.;D;.;D;D;D;.;D
M_CAP	Uncertain	0.19	D
MetaRNN	Uncertain	0.60	D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Benign	0.89	.;L;L;L;L;L;L;L;L;.;.;.;.;.
PrimateAI	Uncertain	0.70	T
PROVEAN	Benign	0.24	N;N;N;N;N;N;N;N;N;N;N;N;N;N
REVEL	Pathogenic	0.66
Sift	Benign	0.49	T;T;T;T;T;T;T;T;T;T;T;T;T;T
Sift4G	Benign	0.83	T;T;T;T;T;T;T;T;T;.;T;T;.;.
Polyphen		1.0, 0.10, 0.13	.;D;B;B;B;B;B;B;B;.;.;.;.;.
Vest4		0.55
MutPred		0.60		Loss of disorder (P = 0.1371);Loss of disorder (P = 0.1371);Loss of disorder (P = 0.1371);Loss of disorder (P = 0.1371);Loss of disorder (P = 0.1371);Loss of disorder (P = 0.1371);Loss of disorder (P = 0.1371);Loss of disorder (P = 0.1371);Loss of disorder (P = 0.1371);Loss of disorder (P = 0.1371);Loss of disorder (P = 0.1371);Loss of disorder (P = 0.1371);Loss of disorder (P = 0.1371);Loss of disorder (P = 0.1371);
MVP		0.88
MPC		1.2
ClinPred		0.62	D
GERP RS		4.9
Varity_R		0.53
gMVP		0.69

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr11-64577506;