19-19218917-A-G

Position:

• chr19-19218917-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_004386.3(NCAN):​c.76A>G​(p.Thr26Ala) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000523 in 1,337,804 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000052 (0 hom.)
• Consequence: NCAN NM_004386.3 missense, splice_region
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.193

Genes affected

NCAN (HGNC:2465): (neurocan) Neurocan is a chondroitin sulfate proteoglycan thought to be involved in the modulation of cell adhesion and migration.[supplied by OMIM, Jul 2002]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.15251416).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NCAN	NM_004386.3	c.76A>G	p.Thr26Ala	missense_variant, splice_region_variant	3/15	ENST00000252575.11	NP_004377.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NCAN	ENST00000252575.11	c.76A>G	p.Thr26Ala	missense_variant, splice_region_variant	3/15	1	NM_004386.3	ENSP00000252575.4

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000523 AC: 7 AN: 1337804 Hom.: 0 Cov.: 31 AF XY: 0.00000613 AC XY: 4 AN XY: 653020

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: 0.00000667

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

Bravo AF: 0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 22, 2023

The c.76A>G (p.T26A) alteration is located in exon 3 (coding exon 2) of the NCAN gene. This alteration results from a A to G substitution at nucleotide position 76, causing the threonine (T) at amino acid position 26 to be replaced by an alanine (A). 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	0.078
BayesDel_addAF	Benign	-0.066	T
BayesDel_noAF	Benign	-0.33
CADD	Benign	14
DANN	Benign	0.90
DEOGEN2	Benign	0.20	T
Eigen	Benign	-0.55
Eigen_PC	Benign	-0.47
FATHMM_MKL	Benign	0.10	N
LIST_S2	Benign	0.41	T
M_CAP	Uncertain	0.10	D
MetaRNN	Benign	0.15	T
MetaSVM	Benign	-0.78	T
MutationAssessor	Benign	1.7	L
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-1.8	N
REVEL	Benign	0.081
Sift	Uncertain	0.028	D
Sift4G	Uncertain	0.045	D
Polyphen		0.23	B
Vest4		0.23
MutPred		0.24		Gain of helix (P = 0.027);
MVP		0.68
MPC		0.44
ClinPred		0.065	T
GERP RS		2.4
Varity_R		0.074
gMVP		0.31

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

Other links and lift over

dbSNP: rs1226557075; hg19: chr19-19329726;