15-23686569-G-C

Variant names:

• chr15-23686569-G-C
• rs145763085
• NM_002487.3:c.649C>G

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_002487.3(NDN):​c.649C>G​(p.Leu217Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,020 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. L217L) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: NDN NM_002487.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.708
• Publications: 0 publications found

Genes affected

NDN (HGNC:7675): (necdin, MAGE family member) This intronless gene is located in the Prader-Willi syndrome deletion region. It is an imprinted gene and is expressed exclusively from the paternal allele. Studies in mouse suggest that the protein encoded by this gene may suppress growth in postmitotic neurons. [provided by RefSeq, Jul 2008]

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002487.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NDN	NM_002487.3	MANE Select	c.649C>G	p.Leu217Val	missense	Exon 1 of 1	NP_002478.1	X5D982

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NDN	ENST00000649030.2	MANE Select	c.649C>G	p.Leu217Val	missense	Exon 1 of 1	ENSP00000497916.1	Q99608

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461020 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 726802

African (AFR) AF: 0.00 AC: 0 AN: 33474

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.00 AC: 0 AN: 86244

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52652

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111944

Other (OTH) AF: 0.00 AC: 0 AN: 60382

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.92
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.40
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.27	T
Eigen	Uncertain	0.19
Eigen_PC	Benign	0.11
FATHMM_MKL	Benign	0.69	D
LIST_S2	Benign	0.76	T
M_CAP	Benign	0.0073	T
MetaRNN	Uncertain	0.49	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.7	L
PhyloP100		0.71
PrimateAI	Uncertain	0.66	T
PROVEAN	Uncertain	-2.8	D
REVEL	Benign	0.17
Sift	Uncertain	0.0010	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.30
MutPred		0.62		Gain of helix (P = 0.2059)
MVP		0.35
MPC		1.7
ClinPred		0.95	D
GERP RS		1.4
Varity_R		0.58
gMVP		0.78
Mutation Taster		=75/25	polymorphism

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

Other links and lift over

dbSNP: rs145763085; hg19: chr15-23931716;