rs78540316

Variant names:

• chr2-50620057-G-A
• rs78540316
• NM_001330078.2:c.1285C>T

Your query was ambiguous. Multiple possible variants found:

• chr2-50620057-G-A
• chr2-50620057-G-C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001330078.2(NRXN1):​c.1285C>T​(p.Pro429Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0034 in 1,609,946 control chromosomes in the GnomAD database, including 25 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P429L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0031 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0034 (24 hom.)
• Consequence: NRXN1 NM_001330078.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: 10.0
• Publications: 15 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.011325926).
• BP6: Variant 2-50620057-G-A is Benign according to our data. Variant chr2-50620057-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 93585.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00312 (475/152246) while in subpopulation NFE AF = 0.00332 (226/68026). AF 95% confidence interval is 0.00297. There are 1 homozygotes in GnomAd4. There are 260 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 24 AR,AD,Unknown gene

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.1285C>T	p.Pro429Ser	missense	Exon 8 of 23	NP_001317007.1	Q9ULB1-5
	NRXN1	NM_001135659.3		c.1405C>T	p.Pro469Ser	missense	Exon 9 of 24	NP_001129131.1	Q9ULB1-3
	NRXN1	NM_001330093.2		c.1282C>T	p.Pro428Ser	missense	Exon 8 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.1285C>T	p.Pro429Ser	missense	Exon 8 of 23	ENSP00000385017.2	Q9ULB1-5
	NRXN1	ENST00000404971.5	TSL:1	c.1405C>T	p.Pro469Ser	missense	Exon 9 of 24	ENSP00000385142.1	Q9ULB1-3
	NRXN1	ENST00000625672.2	TSL:1	c.1261C>T	p.Pro421Ser	missense	Exon 6 of 21	ENSP00000485887.1	Q9ULB1-2

Frequencies

GnomAD3 genomes AF: 0.00312 AC: 475 AN: 152128 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000676

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000852

Gnomad ASJ AF: 0.0130

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00145

Gnomad FIN AF: 0.0143

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00332

Gnomad OTH AF: 0.00144

GnomAD2 exomes AF: 0.00373 AC: 915 AN: 245262 AF XY: 0.00362

Gnomad AFR exome AF: 0.000650

Gnomad AMR exome AF: 0.000565

Gnomad ASJ exome AF: 0.0143

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0155

Gnomad NFE exome AF: 0.00306

Gnomad OTH exome AF: 0.00525

GnomAD4 exome AF: 0.00343 AC: 5004 AN: 1457700 Hom.: 24 Cov.: 30 AF XY: 0.00335 AC XY: 2426 AN XY: 725086

African (AFR) AF: 0.000360 AC: 12 AN: 33340

American (AMR) AF: 0.00115 AC: 51 AN: 44328

Ashkenazi Jewish (ASJ) AF: 0.0136 AC: 352 AN: 25920

East Asian (EAS) AF: 0.00 AC: 0 AN: 39522

South Asian (SAS) AF: 0.00151 AC: 129 AN: 85608

European-Finnish (FIN) AF: 0.0149 AC: 795 AN: 53274

Middle Eastern (MID) AF: 0.000349 AC: 2 AN: 5738

European-Non Finnish (NFE) AF: 0.00310 AC: 3438 AN: 1109770

Other (OTH) AF: 0.00374 AC: 225 AN: 60200

GnomAD4 genome AF: 0.00312 AC: 475 AN: 152246 Hom.: 1 Cov.: 32 AF XY: 0.00349 AC XY: 260 AN XY: 74434

African (AFR) AF: 0.000674 AC: 28 AN: 41558

American (AMR) AF: 0.000851 AC: 13 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.0130 AC: 45 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5162

South Asian (SAS) AF: 0.00145 AC: 7 AN: 4820

European-Finnish (FIN) AF: 0.0143 AC: 152 AN: 10606

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

European-Non Finnish (NFE) AF: 0.00332 AC: 226 AN: 68026

Other (OTH) AF: 0.00142 AC: 3 AN: 2112

Alfa AF: 0.00274 Hom.: 4

Bravo AF: 0.00197

TwinsUK AF: 0.00270 AC: 10

ALSPAC AF: 0.00285 AC: 11

ESP6500AA AF: 0.000508 AC: 2

ESP6500EA AF: 0.00383 AC: 32

ExAC AF: 0.00353 AC: 427

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	3	Pitt-Hopkins-like syndrome 2 (3)
-	-	2	not provided (2)
-	-	1	Inborn genetic diseases (1)
-	-	1	NRXN1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.93
BayesDel_addAF	Benign	-0.080	T
BayesDel_noAF	Uncertain	0.11
CADD	Pathogenic	30
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.47	T
Eigen	Uncertain	0.62
Eigen_PC	Pathogenic	0.71
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	1.0	D
MetaRNN	Benign	0.011	T
MetaSVM	Benign	-0.48	T
MutationAssessor	Benign	1.4	L
PhyloP100		10
PrimateAI	Pathogenic	0.90	D
PROVEAN	Pathogenic	-6.1	D
REVEL	Uncertain	0.43
Sift	Benign	0.087	T
Sift4G	Uncertain	0.0050	D
Polyphen		1.0	D
Vest4		0.74
MVP		0.51
MPC		0.89
ClinPred		0.034	T
GERP RS		6.2
PromoterAI		0.00030	Neutral
Varity_R		0.45
gMVP		0.49
Mutation Taster		=99/1	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: rs78540316; hg19: chr2-50847195; COSMIC: COSV105227047; COSMIC: COSV105227047;