Genetic Variant NM_001330078.2:c.1296C>A (chr2-50620046-G-T) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001330078.2(NRXN1):c.1296C>A(p.Asn432Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,456,596 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. N432N) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

NRXN1
NM_001330078.2 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 8.14

Publications

0 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:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NRXN1	NM_001330078.2 link	c.1296C>A	p.Asn432Lys	missense_variant	Exon 8 of 23	ENST00000401669.7	NP_001317007.1	E7ERL8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NRXN1	ENST00000401669.7 link	c.1296C>A	p.Asn432Lys	missense_variant	Exon 8 of 23	5	NM_001330078.2	ENSP00000385017.2		E7ERL8

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1456596

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

724490

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

33322

American (AMR)

AF:

0.00

AC:

AN:

44202

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25792

East Asian (EAS)

AF:

0.00

AC:

AN:

39526

South Asian (SAS)

AF:

0.00

AC:

AN:

85416

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53230

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5724

European-Non Finnish (NFE)

AF:

0.00000180

AC:

AN:

1109228

Other (OTH)

AF:

0.00

AC:

AN:

60156

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.400

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome 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

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

1.0

BayesDel_addAF

Uncertain

0.084

BayesDel_noAF

Benign

-0.12

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.48

.;T;.;.;T;.;.;T;T

Eigen

Pathogenic

0.69

Eigen_PC

Pathogenic

0.75

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Pathogenic

1.0

D;D;D;D;D;D;D;D;D

M_CAP

Uncertain

0.12

MetaRNN

Uncertain

0.68

D;D;D;D;D;D;D;D;D

MetaSVM

Benign

-0.30

MutationAssessor

Benign

1.2

.;L;.;.;.;.;.;.;.

PhyloP100

8.1

PrimateAI

Pathogenic

0.91

PROVEAN

Pathogenic

-5.0

.;D;D;D;.;.;.;.;.

REVEL

Uncertain

0.44

Sift

Uncertain

0.0010

.;D;D;D;.;.;.;.;.

Sift4G

Pathogenic

0.0

D;D;D;D;D;D;D;D;D

Polyphen

1.0

.;.;D;.;.;.;.;.;.

Vest4

0.86

MutPred

0.54

.;Gain of methylation at N432 (P = 0.0082);.;Gain of methylation at N432 (P = 0.0082);.;.;.;.;.;

MVP

0.35

MPC

0.65

ClinPred

0.98

GERP RS

6.2

PromoterAI

-0.059

Neutral

(source)

Varity_R

0.86

gMVP

0.77

Mutation Taster

=26/74

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.050

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over