19-19219115-C-T

Variant names:

• chr19-19219115-C-T
• rs2228603
• NM_004386.3:c.274C>T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_004386.3(NCAN):​c.274C>T​(p.Pro92Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0676 in 1,612,986 control chromosomes in the GnomAD database, including 3,925 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in UniProt.

• Frequency:
  • Genomes: 𝑓 0.050 (268 hom., cov: 31)
  • Exomes 𝑓: 0.069 (3657 hom.)
• Consequence: NCAN NM_004386.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.69

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 Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.001948297).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.071 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NCAN	NM_004386.3	c.274C>T	p.Pro92Ser	missense_variant	Exon 3 of 15	ENST00000252575.11	NP_004377.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NCAN	ENST00000252575.11	c.274C>T	p.Pro92Ser	missense_variant	Exon 3 of 15	1	NM_004386.3	ENSP00000252575.4

Frequencies

GnomAD3 genomes AF: 0.0504 AC: 7670 AN: 152216 Hom.: 268 Cov.: 31

Gnomad AFR AF: 0.0132

Gnomad AMI AF: 0.104

Gnomad AMR AF: 0.0353

Gnomad ASJ AF: 0.0469

Gnomad EAS AF: 0.0580

Gnomad SAS AF: 0.0641

Gnomad FIN AF: 0.0631

Gnomad MID AF: 0.0601

Gnomad NFE AF: 0.0726

Gnomad OTH AF: 0.0402

GnomAD3 exomes AF: 0.0593 AC: 14817 AN: 249676 Hom.: 541 AF XY: 0.0614 AC XY: 8295 AN XY: 135038

Gnomad AFR exome AF: 0.0130

Gnomad AMR exome AF: 0.0229

Gnomad ASJ exome AF: 0.0527

Gnomad EAS exome AF: 0.0625

Gnomad SAS exome AF: 0.0577

Gnomad FIN exome AF: 0.0622

Gnomad NFE exome AF: 0.0774

Gnomad OTH exome AF: 0.0550

GnomAD4 exome AF: 0.0694 AC: 101300 AN: 1460652 Hom.: 3657 Cov.: 32 AF XY: 0.0691 AC XY: 50220 AN XY: 726508

Gnomad4 AFR exome AF: 0.0113

Gnomad4 AMR exome AF: 0.0231

Gnomad4 ASJ exome AF: 0.0526

Gnomad4 EAS exome AF: 0.0587

Gnomad4 SAS exome AF: 0.0586

Gnomad4 FIN exome AF: 0.0667

Gnomad4 NFE exome AF: 0.0754

Gnomad4 OTH exome AF: 0.0601

GnomAD4 genome AF: 0.0504 AC: 7674 AN: 152334 Hom.: 268 Cov.: 31 AF XY: 0.0503 AC XY: 3749 AN XY: 74482

Gnomad4 AFR AF: 0.0132

Gnomad4 AMR AF: 0.0353

Gnomad4 ASJ AF: 0.0469

Gnomad4 EAS AF: 0.0582

Gnomad4 SAS AF: 0.0640

Gnomad4 FIN AF: 0.0631

Gnomad4 NFE AF: 0.0726

Gnomad4 OTH AF: 0.0412

Alfa AF: 0.0669 Hom.: 702

Bravo AF: 0.0480

TwinsUK AF: 0.0817 AC: 303

ALSPAC AF: 0.0682 AC: 263

ESP6500AA AF: 0.0138 AC: 61

ESP6500EA AF: 0.0741 AC: 637

ExAC AF: 0.0631 AC: 7666

EpiCase AF: 0.0703

EpiControl AF: 0.0674

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.30
BayesDel_addAF	Benign	-0.71	T
BayesDel_noAF	Benign	-0.73
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Benign	0.18	T
Eigen	Benign	0.10
Eigen_PC	Benign	0.17
FATHMM_MKL	Benign	0.74	D
LIST_S2	Benign	0.70	T
MetaRNN	Benign	0.0019	T
MetaSVM	Benign	-0.60	T
MutationAssessor	Benign	0.61	N
PrimateAI	Benign	0.44	T
PROVEAN	Benign	-2.0	N
REVEL	Benign	0.098
Sift	Benign	0.23	T
Sift4G	Benign	1.0	T
Polyphen		0.96	D
Vest4		0.093
MPC		1.2
ClinPred		0.035	T
GERP RS		4.7
Varity_R		0.18
gMVP		0.56

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: rs2228603; hg19: chr19-19329924; COSMIC: COSV53050180;