Genetic Variant NCAN:p.Pro92Ser (chr19-19219115-C-T) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

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. 14/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.050 ( 268 hom., cov: 31)

Exomes 𝑓: 0.069 ( 3657 hom. )

Consequence

NCAN
NM_004386.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.69

Publications

152 publications found

Variant links:

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]

NCAN links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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 link	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 link	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.:

show subpopulations

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

GnomAD2 exomes

AF:

0.0593

AC:

14817

AN:

249676

AF XY:

0.0614

show subpopulations

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 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.:

AF XY:

0.0691

AC XY:

50220

AN XY:

726508

show subpopulations

African (AFR)

AF:

0.0113

AC:

378

AN:

33470

American (AMR)

AF:

0.0231

AC:

1032

AN:

44642

Ashkenazi Jewish (ASJ)

AF:

0.0526

AC:

1371

AN:

26050

East Asian (EAS)

AF:

0.0587

AC:

2329

AN:

39682

South Asian (SAS)

AF:

0.0586

AC:

5044

AN:

86096

European-Finnish (FIN)

AF:

0.0667

AC:

3552

AN:

53234

Middle Eastern (MID)

AF:

0.0283

AC:

163

AN:

5760

European-Non Finnish (NFE)

AF:

0.0754

AC:

83807

AN:

1111376

Other (OTH)

AF:

0.0601

AC:

3624

AN:

60342

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.494

Heterozygous variant carriers

5908

11816

17725

23633

29541

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

3058

6116

9174

12232

15290

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0504

AC:

7674

AN:

152334

Hom.:

268

Cov.:

AF XY:

0.0503

AC XY:

3749

AN XY:

74482

show subpopulations

African (AFR)

AF:

0.0132

AC:

548

AN:

41592

American (AMR)

AF:

0.0353

AC:

540

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.0469

AC:

163

AN:

3472

East Asian (EAS)

AF:

0.0582

AC:

301

AN:

5176

South Asian (SAS)

AF:

0.0640

AC:

309

AN:

4830

European-Finnish (FIN)

AF:

0.0631

AC:

670

AN:

10624

Middle Eastern (MID)

AF:

0.0680

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0726

AC:

4941

AN:

68018

Other (OTH)

AF:

0.0412

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.495

Heterozygous variant carriers

383

766

1149

1532

1915

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

176

264

352

440

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0667

Hom.:

1420

Bravo

AF:

0.0480

TwinsUK

AF:

0.0817

AC:

303

ALSPAC

AF:

0.0682

AC:

263

ESP6500AA

AF:

0.0138

AC:

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

BayesDel_noAF

Benign

-0.73

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.18

Eigen

Benign

0.10

Eigen_PC

Benign

0.17

FATHMM_MKL

Benign

0.74

LIST_S2

Benign

0.70

MetaRNN

Benign

0.0019

MetaSVM

Benign

-0.60

MutationAssessor

Benign

0.61

PhyloP100

1.7

PrimateAI

Benign

0.44

PROVEAN

Benign

-2.0

REVEL

Benign

0.098

Sift

Benign

0.23

Sift4G

Benign

1.0

Polyphen

0.96

Vest4

0.093

MPC

1.2

ClinPred

0.035

GERP RS

4.7

Varity_R

0.18

gMVP

0.56

Mutation Taster

=96/4

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over