rs202006815

Variant names:

• chr2-50053339-T-A
• rs202006815
• NM_001330078.2:c.4060A>T

Your query was ambiguous. Multiple possible variants found:

• chr2-50053339-T-A
• chr2-50053339-T-C

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS1

The NM_001330078.2(NRXN1):​c.4060A>T​(p.Thr1354Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000737 in 1,614,024 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00012 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000068 (0 hom.)
• Consequence: NRXN1 NM_001330078.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:2
• Conservation: PhyloP100: 8.02
• Publications: 5 publications found

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: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae)
• autism

  Inheritance: AD Classification: MODERATE Submitted by: G2P
• schizophrenia

  Inheritance: Unknown Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

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

• BP4: Computational evidence support a benign effect (MetaRNN=0.010817081).
• BP6: Variant 2-50053339-T-A is Benign according to our data. Variant chr2-50053339-T-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 336541.
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.000125 (19/152290) while in subpopulation EAS AF = 0.00348 (18/5174). AF 95% confidence interval is 0.00225. There are 0 homozygotes in GnomAd4. There are 12 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001330078.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NRXN1	NM_001330078.2	MANE Select	c.4060A>T	p.Thr1354Ser	missense	Exon 21 of 23	NP_001317007.1	Q9ULB1-5
	NRXN1	NM_001135659.3		c.4180A>T	p.Thr1394Ser	missense	Exon 22 of 24	NP_001129131.1	Q9ULB1-3
	NRXN1	NM_001330093.2		c.4057A>T	p.Thr1353Ser	missense	Exon 21 of 23	NP_001317022.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NRXN1	ENST00000401669.7	TSL:5 MANE Select	c.4060A>T	p.Thr1354Ser	missense	Exon 21 of 23	ENSP00000385017.2	Q9ULB1-5
	NRXN1	ENST00000404971.5	TSL:1	c.4180A>T	p.Thr1394Ser	missense	Exon 22 of 24	ENSP00000385142.1	Q9ULB1-3
	NRXN1	ENST00000625672.2	TSL:1	c.4036A>T	p.Thr1346Ser	missense	Exon 19 of 21	ENSP00000485887.1	Q9ULB1-2

Frequencies

GnomAD3 genomes AF: 0.000131 AC: 20 AN: 152172 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00366

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000239 AC: 60 AN: 251128 AF XY: 0.000221

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00315

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.0000684 AC: 100 AN: 1461734 Hom.: 0 Cov.: 32 AF XY: 0.0000646 AC XY: 47 AN XY: 727158

African (AFR) AF: 0.00 AC: 0 AN: 33468

American (AMR) AF: 0.00 AC: 0 AN: 44710

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00242 AC: 96 AN: 39696

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111904

Other (OTH) AF: 0.0000331 AC: 2 AN: 60382

GnomAD4 genome AF: 0.000125 AC: 19 AN: 152290 Hom.: 0 Cov.: 33 AF XY: 0.000161 AC XY: 12 AN XY: 74476

African (AFR) AF: 0.00 AC: 0 AN: 41568

American (AMR) AF: 0.00 AC: 0 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00348 AC: 18 AN: 5174

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68018

Other (OTH) AF: 0.000473 AC: 1 AN: 2112

Alfa AF: 0.000101 Hom.: 0

Bravo AF: 0.000219

ExAC AF: 0.000239 AC: 29

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	-	Inborn genetic diseases (1)
-	-	1	not provided (1)
-	1	-	Pitt-Hopkins-like syndrome (1)
-	-	1	Pitt-Hopkins-like syndrome 2 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.50
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.21
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Benign	0.055	T
Eigen	Benign	0.18
Eigen_PC	Uncertain	0.35
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.92	D
M_CAP	Benign	0.023	T
MetaRNN	Benign	0.011	T
MetaSVM	Benign	-0.59	T
MutationAssessor	Benign	1.4	L
PhyloP100		8.0
PrimateAI	Uncertain	0.59	T
PROVEAN	Benign	-2.3	N
REVEL	Benign	0.15
Sift	Benign	0.18	T
Sift4G	Uncertain	0.030	D
Polyphen		0.14	B
Vest4		0.43
MutPred		0.21		Gain of glycosylation at T1324 (P = 0.043)
MVP		0.38
MPC		1.4
ClinPred		0.10	T
GERP RS		5.5
Varity_R		0.16
gMVP		0.43
Mutation Taster		=39/61	disease causing

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

Other links and lift over

dbSNP: rs202006815; hg19: chr2-50280477;