chr1-35559200-C-T

Variant names:

• chr1-35559200-C-T
• NM_014284.3:c.127C>T

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_014284.3(NCDN):​c.127C>T​(p.Leu43Phe) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 30)
• Consequence: NCDN NM_014284.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.95
• Publications: 0 publications found

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 Gene-Disease associations (from GenCC):

• neurodevelopmental disorder with infantile epileptic spasms

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• autosomal recessive non-syndromic intellectual disability

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.903

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_014284.3. 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
	NCDN	NM_014284.3	MANE Select	c.127C>T	p.Leu43Phe	missense	Exon 2 of 7	NP_055099.1	Q9UBB6-1
	NCDN	NM_001014839.2		c.127C>T	p.Leu43Phe	missense	Exon 3 of 8	NP_001014839.1	Q9UBB6-1
	NCDN	NM_001014841.2		c.76C>T	p.Leu26Phe	missense	Exon 2 of 7	NP_001014841.1	Q9UBB6-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NCDN	ENST00000373243.7	TSL:1 MANE Select	c.127C>T	p.Leu43Phe	missense	Exon 2 of 7	ENSP00000362340.2	Q9UBB6-1
	NCDN	ENST00000356090.8	TSL:1	c.127C>T	p.Leu43Phe	missense	Exon 3 of 8	ENSP00000348394.4	Q9UBB6-1
	NCDN	ENST00000373253.7	TSL:1	c.76C>T	p.Leu26Phe	missense	Exon 2 of 7	ENSP00000362350.3	Q9UBB6-2

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 30

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Neurodevelopmental disorder with infantile epileptic spasms (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.50
BayesDel_addAF	Pathogenic	0.18	D
BayesDel_noAF	Uncertain	0.020
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.66	D
Eigen	Uncertain	0.38
Eigen_PC	Uncertain	0.41
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.76	T
M_CAP	Benign	0.039	D
MetaRNN	Pathogenic	0.90	D
MetaSVM	Uncertain	-0.27	T
MutationAssessor	Benign	2.0	M
PhyloP100		5.0
PrimateAI	Uncertain	0.77	T
PROVEAN	Uncertain	-2.9	D
REVEL	Uncertain	0.58
Sift	Benign	0.068	T
Sift4G	Benign	0.20	T
Polyphen		0.89	P
Vest4		0.51
MutPred		0.83		Loss of disorder (P = 0.1411)
MVP		0.72
MPC		1.3
ClinPred		0.94	D
GERP RS		4.7
Varity_R		0.61
gMVP		0.72
Mutation Taster		=51/49	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

hg19: chr1-36024801;