chr1-35560376-G-T

Variant names:

• chr1-35560376-G-T
• rs138059318
• NM_014284.3:c.225G>T

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 0P and 11B. BP4_Strong BP6_Moderate BP7 BS2

The NM_014284.3(NCDN):​c.225G>T​(p.Arg75Arg) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00561 in 1,614,026 control chromosomes in the GnomAD database, including 37 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0035 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0058 (37 hom.)
• Consequence: NCDN NM_014284.3 synonymous
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 2.50
• 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: Benign. The variant received -11 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.53).
• BP6: Variant 1-35560376-G-T is Benign according to our data. Variant chr1-35560376-G-T is described in ClinVar as Likely_benign. ClinVar VariationId is 1879083.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=2.5 with no splicing effect.
• BS2: High Homozygotes in GnomAdExome4 at 37 AD,AR gene

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.225G>T	p.Arg75Arg	synonymous	Exon 3 of 7	NP_055099.1	Q9UBB6-1
	NCDN	NM_001014839.2		c.225G>T	p.Arg75Arg	synonymous	Exon 4 of 8	NP_001014839.1	Q9UBB6-1
	NCDN	NM_001014841.2		c.174G>T	p.Arg58Arg	synonymous	Exon 3 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.225G>T	p.Arg75Arg	synonymous	Exon 3 of 7	ENSP00000362340.2	Q9UBB6-1
	NCDN	ENST00000356090.8	TSL:1	c.225G>T	p.Arg75Arg	synonymous	Exon 4 of 8	ENSP00000348394.4	Q9UBB6-1
	NCDN	ENST00000373253.7	TSL:1	c.174G>T	p.Arg58Arg	synonymous	Exon 3 of 7	ENSP00000362350.3	Q9UBB6-2

Frequencies

GnomAD3 genomes AF: 0.00346 AC: 526 AN: 152236 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00118

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00105

Gnomad ASJ AF: 0.0109

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.0000941

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00613

Gnomad OTH AF: 0.00143

GnomAD2 exomes AF: 0.00322 AC: 810 AN: 251304 AF XY: 0.00327

Gnomad AFR exome AF: 0.000800

Gnomad AMR exome AF: 0.00124

Gnomad ASJ exome AF: 0.00893

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000326

Gnomad NFE exome AF: 0.00534

Gnomad OTH exome AF: 0.00489

GnomAD4 exome AF: 0.00584 AC: 8535 AN: 1461672 Hom.: 37 Cov.: 32 AF XY: 0.00572 AC XY: 4159 AN XY: 727158

African (AFR) AF: 0.000836 AC: 28 AN: 33480

American (AMR) AF: 0.00152 AC: 68 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00995 AC: 260 AN: 26136

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.000696 AC: 60 AN: 86258

European-Finnish (FIN) AF: 0.000789 AC: 42 AN: 53208

Middle Eastern (MID) AF: 0.00121 AC: 7 AN: 5768

European-Non Finnish (NFE) AF: 0.00701 AC: 7797 AN: 1112008

Other (OTH) AF: 0.00450 AC: 272 AN: 60392

GnomAD4 genome AF: 0.00345 AC: 526 AN: 152354 Hom.: 0 Cov.: 32 AF XY: 0.00302 AC XY: 225 AN XY: 74496

African (AFR) AF: 0.00118 AC: 49 AN: 41586

American (AMR) AF: 0.00105 AC: 16 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.0109 AC: 38 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.000414 AC: 2 AN: 4830

European-Finnish (FIN) AF: 0.0000941 AC: 1 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00613 AC: 417 AN: 68030

Other (OTH) AF: 0.00142 AC: 3 AN: 2116

Alfa AF: 0.00563 Hom.: 0

Bravo AF: 0.00327

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00534

EpiControl AF: 0.00533

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.53
CADD	Benign	7.7
DANN	Benign	0.87
PhyloP100		2.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=100/0	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: rs138059318; hg19: chr1-36025977; COSMIC: COSV57846423; COSMIC: COSV57846423;