2-49922195-G-T

Variant names:

• chr2-49922195-G-T
• rs749698919
• NM_001330078.2:c.4273C>A
• NRXN1 p.Arg1425Arg

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP6_Moderate

The NM_001330078.2(NRXN1):​c.4273C>A​(p.Arg1425Arg) variant causes a synonymous change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely benign (★). Synonymous variant affecting the same amino acid position (i.e. R1425R) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: NRXN1 NM_001330078.2 synonymous
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 8.11
• Publications: 8 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: 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)

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP6: Variant 2-49922195-G-T is Benign according to our data. Variant chr2-49922195-G-T is described in ClinVar as Likely_benign. ClinVar VariationId is 3630342.Status of the report is criteria_provided_single_submitter, 1 stars.

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.4273C>A	p.Arg1425Arg	synonymous	Exon 23 of 23	NP_001317007.1	Q9ULB1-5
	NRXN1	NM_001135659.3		c.4393C>A	p.Arg1465Arg	synonymous	Exon 24 of 24	NP_001129131.1	Q9ULB1-3
	NRXN1	NM_001330093.2		c.4270C>A	p.Arg1424Arg	synonymous	Exon 23 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.4273C>A	p.Arg1425Arg	synonymous	Exon 23 of 23	ENSP00000385017.2	Q9ULB1-5
	NRXN1	ENST00000404971.5	TSL:1	c.4393C>A	p.Arg1465Arg	synonymous	Exon 24 of 24	ENSP00000385142.1	Q9ULB1-3
	NRXN1	ENST00000625672.2	TSL:1	c.4240C>A	p.Arg1414Arg	synonymous	Exon 21 of 21	ENSP00000485887.1	Q9ULB1-2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	Pitt-Hopkins-like syndrome 2 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.40
CADD	Benign	10
DANN	Benign	0.65
PhyloP100		8.1
Mutation Taster		=41/59	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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs749698919;

hg19: chr2-50149333;

COSMIC: COSV60499062;