chr11-64807893-G-C

Variant names:

• chr11-64807893-G-C
• NM_001370259.2:c.652C>G

Variant summary

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

The NM_001370259.2(MEN1):​c.652C>G​(p.Arg218Gly) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,736 control chromosomes in the GnomAD database, with no homozygous occurrence. 2/3 splice prediction tools predict no significant impact on normal splicing. 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. R218L) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: MEN1 NM_001370259.2 missense, splice_region
• Scores: Splicing: ADA: 0.1378
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.15

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 chr11-64807892-C-A 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.652C>G	p.Arg218Gly	missense_variant, splice_region_variant	Exon 3 of 10	ENST00000450708.7	NP_001357188.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MEN1	ENST00000450708.7	c.652C>G	p.Arg218Gly	missense_variant, splice_region_variant	Exon 3 of 10	5	NM_001370259.2	ENSP00000394933.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461736 Hom.: 0 Cov.: 33 AF XY: 0.00000138 AC XY: 1 AN XY: 727162

Gnomad4 AFR exome AF: 0.00

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: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.67
BayesDel_addAF	Pathogenic	0.26	D
BayesDel_noAF	Uncertain	0.13
CADD	Pathogenic	27
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.80	D;.;.;.;D;D;D;D;D;.;D
Eigen	Benign	-0.31
Eigen_PC	Benign	-0.17
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.96	D;.;.;D;.;.;D;.;D;D;D
M_CAP	Pathogenic	0.51	D
MetaRNN	Uncertain	0.60	D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	0.92	D
MutationAssessor	Benign	0.94	.;.;.;.;L;L;L;L;.;.;.
PrimateAI	Uncertain	0.72	T
PROVEAN	Uncertain	-3.8	D;D;D;D;D;D;D;D;D;D;D
REVEL	Uncertain	0.63
Sift	Benign	0.16	T;T;T;T;T;T;T;T;T;T;T
Sift4G	Benign	0.27	T;T;T;T;T;T;T;T;.;T;T
Polyphen		0.0070, 0.0090	.;B;B;B;B;B;B;B;.;.;.
Vest4		0.34
MutPred		0.61		.;.;.;.;Gain of sheet (P = 0.0061);Gain of sheet (P = 0.0061);Gain of sheet (P = 0.0061);Gain of sheet (P = 0.0061);.;.;.;
MVP		0.98
MPC		1.3
ClinPred		0.54	D
GERP RS		3.8
Varity_R		0.65
gMVP		0.86

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.14
dbscSNV1_RF	Benign	0.31
SpliceAI score (max)		0.34		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.34		Position offset: 12
DS_DL_spliceai		0.20		Position offset: -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: chr11-64575365;