chr2-50346909-G-A

Variant names:

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_StrongBP6BS1

The ENST00000342183.9(NRXN1):c.41C>T(p.Ser14Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000384 in 1,295,284 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00026 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00040 ( 0 hom. )

Consequence

NRXN1
ENST00000342183.9 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:3

Conservation

PhyloP100: 3.29

Publications

5 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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.005674839).

BP6

Variant 2-50346909-G-A is Benign according to our data. Variant chr2-50346909-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 206264.

BS1

Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.000258 (39/151024) while in subpopulation SAS AF = 0.000624 (3/4808). AF 95% confidence interval is 0.000306. There are 0 homozygotes in GnomAd4. There are 21 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000342183.9. 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.3365-109939C>T		intron	N/A	NP_001317007.1
NRXN1	NM_001330092.2		c.41C>T	p.Ser14Leu	missense	Exon 1 of 7	NP_001317021.1
NRXN1	NM_001330091.2		c.41C>T	p.Ser14Leu	missense	Exon 1 of 7	NP_001317020.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
NRXN1	ENST00000342183.9	TSL:1	c.41C>T	p.Ser14Leu	missense	Exon 1 of 6	ENSP00000341184.5
NRXN1	ENST00000401669.7	TSL:5 MANE Select	c.3365-109939C>T		intron	N/A	ENSP00000385017.2
NRXN1	ENST00000404971.5	TSL:1	c.3485-109939C>T		intron	N/A	ENSP00000385142.1

Frequencies

GnomAD3 genomes

AF:

0.000258

AC:

AN:

150916

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000121

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000661

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000623

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000429

Gnomad OTH

AF:

0.000482

GnomAD2 exomes

AF:

0.000627

AC:

AN:

30310

AF XY:

0.000489

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.000459

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000973

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000401

AC:

459

AN:

1144260

Hom.:

Cov.:

AF XY:

0.000398

AC XY:

221

AN XY:

555956

show subpopulations

African (AFR)

AF:

0.0000434

AC:

AN:

23050

American (AMR)

AF:

0.0000954

AC:

AN:

10484

Ashkenazi Jewish (ASJ)

AF:

0.0000651

AC:

AN:

15356

East Asian (EAS)

AF:

0.00

AC:

AN:

23216

South Asian (SAS)

AF:

0.000904

AC:

AN:

37628

European-Finnish (FIN)

AF:

0.0000316

AC:

AN:

31634

Middle Eastern (MID)

AF:

0.00251

AC:

AN:

3184

European-Non Finnish (NFE)

AF:

0.000408

AC:

389

AN:

954532

Other (OTH)

AF:

0.000531

AC:

AN:

45176

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.539

Heterozygous variant carriers

119

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

100

<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:

0.000258

AC:

AN:

151024

Hom.:

Cov.:

AF XY:

0.000285

AC XY:

AN XY:

73774

show subpopulations

African (AFR)

AF:

0.000121

AC:

AN:

41384

American (AMR)

AF:

0.0000660

AC:

AN:

15148

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3454

East Asian (EAS)

AF:

0.00

AC:

AN:

5106

South Asian (SAS)

AF:

0.000624

AC:

AN:

4808

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10182

Middle Eastern (MID)

AF:

0.00

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.000429

AC:

AN:

67642

Other (OTH)

AF:

0.000477

AC:

AN:

2096

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.520

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.000356

Hom.:

Bravo

AF:

0.000317

ExAC

AF:

0.000515

AC:

ClinVar

ClinVar submissions as Germline

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Inborn genetic diseases (1)

Pitt-Hopkins-like syndrome 2 (1)

Pitt-Hopkins-like syndrome 2;C3808494:Chromosome 2p16.3 deletion syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.17

BayesDel_addAF

Benign

-0.42

BayesDel_noAF

Benign

-0.43

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.22

Eigen

Benign

-0.49

Eigen_PC

Benign

-0.34

FATHMM_MKL

Uncertain

0.88

LIST_S2

Benign

0.83

MetaRNN

Benign

0.0057

MetaSVM

Benign

-1.1

MutationAssessor

Benign

-0.34

PhyloP100

3.3

PROVEAN

Benign

-1.7

REVEL

Benign

0.068

Sift

Pathogenic

0.0

Sift4G

Benign

0.11

Polyphen

0.0

Vest4

0.28

MutPred

0.28

Loss of glycosylation at S14 (P = 0.0048)

MVP

0.043

ClinPred

0.19

GERP RS

3.0

Mutation Taster

=95/5

polymorphism

(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

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over