Genetic Variant NCDN:p.Arg140Trp (chr1-35560569-C-T) – ACMG Classification: Likely_benign (-5 pts)

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4BS2

The NM_014284.3(NCDN):c.418C>T(p.Arg140Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000062 in 1,613,306 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 Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R140P) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000041 ( 0 hom. )

Consequence

NCDN
NM_014284.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.859

Variant links:

Genes affected

NCDN (HGNC:17597): (neurochondrin) This gene encodes a leucine-rich cytoplasmic protein, which is highly similar to a mouse protein that negatively regulates Ca/calmodulin-dependent protein kinase II phosphorylation and may be essential for spatial learning processes. Several alternatively spliced transcript variants of this gene have been described. [provided by RefSeq, Jul 2008]

NCDN links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -5 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.3235211).

BS2

High AC in GnomAdExome4 at 6 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NCDN	NM_014284.3 link	c.418C>T	p.Arg140Trp	missense_variant	Exon 3 of 7	ENST00000373243.7	NP_055099.1	Q9UBB6-1
NCDN	NM_001014839.2 link	c.418C>T	p.Arg140Trp	missense_variant	Exon 4 of 8		NP_001014839.1	Q9UBB6-1
NCDN	NM_001014841.2 link	c.367C>T	p.Arg123Trp	missense_variant	Exon 3 of 7		NP_001014841.1	Q9UBB6-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NCDN	ENST00000373243.7 link	c.418C>T	p.Arg140Trp	missense_variant	Exon 3 of 7	1	NM_014284.3	ENSP00000362340.2		Q9UBB6-1

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152182

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000724

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:

0.0000942

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000411

AC:

AN:

1461124

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

726934

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

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:

0.0000190

Gnomad4 NFE exome

AF:

0.00000180

Gnomad4 OTH exome

AF:

0.0000331

GnomAD4 genome

AF:

0.0000263

AC:

AN:

152182

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74324

show subpopulations

Gnomad4 AFR

AF:

0.0000724

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.0000942

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000189

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Feb 06, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.418C>T (p.R140W) alteration is located in exon 3 (coding exon 3) of the NCDN gene. This alteration results from a C to T substitution at nucleotide position 418, causing the arginine (R) at amino acid position 140 to be replaced by a tryptophan (W). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Benign

-0.0017

BayesDel_noAF

Benign

-0.24

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.30

.;T;T;.

Eigen

Benign

0.18

Eigen_PC

Benign

0.17

FATHMM_MKL

Uncertain

0.93

LIST_S2

Uncertain

0.91

D;.;D;D

M_CAP

Benign

0.014

MetaRNN

Benign

0.32

T;T;T;T

MetaSVM

Benign

-0.63

MutationAssessor

Benign

0.69

.;N;N;.

PrimateAI

Uncertain

0.63

PROVEAN

Uncertain

-2.4

N;N;N;N

REVEL

Benign

0.14

Sift

Uncertain

0.026

D;D;D;D

Sift4G

Uncertain

0.035

D;D;D;D

Polyphen

0.99

.;D;D;.

Vest4

0.24

MutPred

0.52

.;Gain of catalytic residue at P143 (P = 0.0249);Gain of catalytic residue at P143 (P = 0.0249);.;

MVP

0.26

MPC

2.0

ClinPred

0.86

GERP RS

2.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.11

gMVP

0.37

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over