rs199784029

Variant names:

• chr2-51027952-G-A
• rs199784029
• NM_001330078.2:c.322C>T

Your query was ambiguous. Multiple possible variants found:

• chr2-51027952-G-A
• chr2-51027952-G-C
• chr2-51027952-G-T

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.322C>T​(p.Pro108Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000452 in 1,603,282 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P108L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0013 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00036 (0 hom.)
• Consequence: NRXN1 NM_001330078.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4 B:4
• Conservation: PhyloP100: 2.04
• Publications: 2 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=0.011961669).
• BP6: Variant 2-51027952-G-A is Benign according to our data. Variant chr2-51027952-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 93599.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00132 (201/152298) while in subpopulation AFR AF = 0.00373 (155/41580). AF 95% confidence interval is 0.00325. There are 0 homozygotes in GnomAd4. There are 97 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.322C>T	p.Pro108Ser	missense	Exon 2 of 23	NP_001317007.1	Q9ULB1-5
	NRXN1	NM_001135659.3		c.322C>T	p.Pro108Ser	missense	Exon 2 of 24	NP_001129131.1	Q9ULB1-3
	NRXN1	NM_001330093.2		c.322C>T	p.Pro108Ser	missense	Exon 2 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.322C>T	p.Pro108Ser	missense	Exon 2 of 23	ENSP00000385017.2	Q9ULB1-5
	NRXN1	ENST00000404971.5	TSL:1	c.322C>T	p.Pro108Ser	missense	Exon 2 of 24	ENSP00000385142.1	Q9ULB1-3
	NRXN1	ENST00000625672.2	TSL:1	c.322C>T	p.Pro108Ser	missense	Exon 1 of 21	ENSP00000485887.1	Q9ULB1-2

Frequencies

GnomAD3 genomes AF: 0.00131 AC: 200 AN: 152180 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00371

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000850

Gnomad ASJ AF: 0.000865

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000338

Gnomad OTH AF: 0.00287

GnomAD2 exomes AF: 0.000743 AC: 174 AN: 234050 AF XY: 0.000636

Gnomad AFR exome AF: 0.00402

Gnomad AMR exome AF: 0.00193

Gnomad ASJ exome AF: 0.000716

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000288

Gnomad OTH exome AF: 0.00189

GnomAD4 exome AF: 0.000361 AC: 524 AN: 1450984 Hom.: 0 Cov.: 31 AF XY: 0.000329 AC XY: 238 AN XY: 722310

African (AFR) AF: 0.00380 AC: 127 AN: 33456

American (AMR) AF: 0.00177 AC: 79 AN: 44662

Ashkenazi Jewish (ASJ) AF: 0.000460 AC: 12 AN: 26066

East Asian (EAS) AF: 0.00 AC: 0 AN: 39686

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86202

European-Finnish (FIN) AF: 0.0000231 AC: 1 AN: 43332

Middle Eastern (MID) AF: 0.00226 AC: 13 AN: 5764

European-Non Finnish (NFE) AF: 0.000222 AC: 247 AN: 1111544

Other (OTH) AF: 0.000713 AC: 43 AN: 60272

GnomAD4 genome AF: 0.00132 AC: 201 AN: 152298 Hom.: 0 Cov.: 33 AF XY: 0.00130 AC XY: 97 AN XY: 74458

African (AFR) AF: 0.00373 AC: 155 AN: 41580

American (AMR) AF: 0.000849 AC: 13 AN: 15314

Ashkenazi Jewish (ASJ) AF: 0.000865 AC: 3 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5124

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

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10630

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.000338 AC: 23 AN: 68028

Other (OTH) AF: 0.00284 AC: 6 AN: 2114

Alfa AF: 0.000651 Hom.: 0

Bravo AF: 0.00162

ESP6500AA AF: 0.00366 AC: 15

ESP6500EA AF: 0.000358 AC: 3

ExAC AF: 0.000773 AC: 93

EpiCase AF: 0.000436

EpiControl AF: 0.000415

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	1	not provided (2)
-	1	1	Pitt-Hopkins-like syndrome 2 (2)
-	1	-	Inborn genetic diseases (1)
-	-	1	Intellectual disability (1)
-	-	1	NRXN1-related disorder (1)
-	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	0.12
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.24
CADD	Benign	22
DANN	Benign	0.91
DEOGEN2	Benign	0.19	T
Eigen	Benign	-0.33
Eigen_PC	Benign	-0.17
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.91	D
MetaRNN	Benign	0.012	T
MetaSVM	Benign	-0.90	T
MutationAssessor	Benign	1.2	L
PhyloP100		2.0
PrimateAI	Uncertain	0.62	T
PROVEAN	Benign	-0.93	N
REVEL	Benign	0.24
Sift	Benign	0.51	T
Sift4G	Benign	0.14	T
Polyphen		0.012	B
Vest4		0.28
MVP		0.53
MPC		0.63
ClinPred		0.0050	T
GERP RS		5.0
PromoterAI		0.020	Neutral
Varity_R		0.067
gMVP		0.47
Mutation Taster		=73/27	polymorphism

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: rs199784029; hg19: chr2-51255090; COSMIC: COSV104433968; COSMIC: COSV104433968;