dbSNP rs2303298: NRXN1:p.Pro300Pro (chr2-50623548-G-A) – ACMG Classification: Benign (-19 pts)

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BA1

The NM_001135659.3(NRXN1):c.999C>T(p.Pro333Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0119 in 1,613,166 control chromosomes in the GnomAD database, including 931 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.020 ( 91 hom., cov: 32)

Exomes 𝑓: 0.011 ( 840 hom. )

Consequence

NRXN1
NM_001135659.3 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: 0.729

Publications

13 publications found

Variant links:

Genes affected

NRXN1 (HGNC:8008): (neurexin 1) This gene encodes a single-pass type I membrane protein that belongs to the neurexin family. Neurexins are cell-surface receptors that bind neuroligins to form Ca(2+)-dependent neurexin/neuroligin complexes at synapses in the central nervous system. This complex is required for efficient neurotransmission and is involved in the formation of synaptic contacts. Three members of this gene family have been studied in detail and are estimated to generate over 3,000 variants through the use of two alternative promoters (alpha and beta) and extensive alternative splicing in each family member. Recently, a third promoter (gamma) was identified for this gene in the 3' region. Mutations in this gene are associated with Pitt-Hopkins-like syndrome-2 and may contribute to susceptibility to schizophrenia. [provided by RefSeq, Aug 2016]

NRXN1 Gene-Disease associations (from GenCC):

complex neurodevelopmental disorder
Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
chromosome 2p16.3 deletion syndrome
Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
Pitt-Hopkins-like syndrome 2
Inheritance: AR Classification: STRONG, MODERATE Submitted by: G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae)
autism
Inheritance: AD Classification: MODERATE Submitted by: G2P
schizophrenia
Inheritance: Unknown Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

NRXN1 links:

ENSG00000283058 (HGNC:):

ENSG00000283058 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -19 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.46).

BP6

Variant 2-50623548-G-A is Benign according to our data. Variant chr2-50623548-G-A is described in ClinVar as Benign. ClinVar VariationId is 129827.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=0.729 with no splicing effect.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.103 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001135659.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
NRXN1	NM_001330078.2	MANE Select	c.900C>T	p.Pro300Pro	synonymous	Exon 6 of 23	NP_001317007.1
NRXN1	NM_001135659.3		c.999C>T	p.Pro333Pro	synonymous	Exon 7 of 24	NP_001129131.1
NRXN1	NM_001330093.2		c.897C>T	p.Pro299Pro	synonymous	Exon 6 of 23	NP_001317022.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
NRXN1	ENST00000401669.7	TSL:5 MANE Select	c.900C>T	p.Pro300Pro	synonymous	Exon 6 of 23	ENSP00000385017.2
NRXN1	ENST00000404971.5	TSL:1	c.999C>T	p.Pro333Pro	synonymous	Exon 7 of 24	ENSP00000385142.1
NRXN1	ENST00000625672.2	TSL:1	c.900C>T	p.Pro300Pro	synonymous	Exon 5 of 21	ENSP00000485887.1

Frequencies

GnomAD3 genomes

AF:

0.0197

AC:

2999

AN:

152084

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0348

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0409

Gnomad ASJ

AF:

0.00721

Gnomad EAS

AF:

0.110

Gnomad SAS

AF:

0.0139

Gnomad FIN

AF:

0.00622

Gnomad MID

AF:

0.0222

Gnomad NFE

AF:

0.00244

Gnomad OTH

AF:

0.0177

GnomAD2 exomes

AF:

0.0251

AC:

6249

AN:

248600

AF XY:

0.0219

show subpopulations

Gnomad AFR exome

AF:

0.0363

Gnomad AMR exome

AF:

0.0837

Gnomad ASJ exome

AF:

0.00826

Gnomad EAS exome

AF:

0.101

Gnomad FIN exome

AF:

0.00743

Gnomad NFE exome

AF:

0.00286

Gnomad OTH exome

AF:

0.0192

GnomAD4 exome

AF:

0.0110

AC:

16110

AN:

1460964

Hom.:

840

Cov.:

AF XY:

0.0107

AC XY:

7769

AN XY:

726798

show subpopulations

African (AFR)

AF:

0.0398

AC:

1330

AN:

33434

American (AMR)

AF:

0.0788

AC:

3518

AN:

44652

Ashkenazi Jewish (ASJ)

AF:

0.00766

AC:

200

AN:

26118

East Asian (EAS)

AF:

0.161

AC:

6401

AN:

39684

South Asian (SAS)

AF:

0.0104

AC:

898

AN:

86252

European-Finnish (FIN)

AF:

0.00787

AC:

420

AN:

53382

Middle Eastern (MID)

AF:

0.00955

AC:

AN:

5760

European-Non Finnish (NFE)

AF:

0.00229

AC:

2544

AN:

1111344

Other (OTH)

AF:

0.0123

AC:

744

AN:

60338

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.490

Heterozygous variant carriers

857

1713

2570

3426

4283

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

242

484

726

968

1210

<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:

0.0198

AC:

3013

AN:

152202

Hom.:

Cov.:

AF XY:

0.0211

AC XY:

1569

AN XY:

74436

show subpopulations

African (AFR)

AF:

0.0351

AC:

1458

AN:

41542

American (AMR)

AF:

0.0410

AC:

626

AN:

15264

Ashkenazi Jewish (ASJ)

AF:

0.00721

AC:

AN:

3468

East Asian (EAS)

AF:

0.110

AC:

567

AN:

5154

South Asian (SAS)

AF:

0.0131

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00622

AC:

AN:

10618

Middle Eastern (MID)

AF:

0.0204

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00244

AC:

166

AN:

68008

Other (OTH)

AF:

0.0170

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

149

299

448

598

747

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

108

144

180

<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:

0.0114

Hom.:

Bravo

AF:

0.0250

Asia WGS

AF:

0.0520

AC:

180

AN:

3478

EpiCase

AF:

0.00235

EpiControl

AF:

0.00314

ClinVar

ClinVar submissions as Germline

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (3)

not specified (3)

Pitt-Hopkins-like syndrome 2 (2)

Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.46

CADD

Benign

9.1

(source)

DANN

Benign

0.65

PhyloP100

0.73

Mutation Taster

=87/13

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over