chr11-64713324-G-A

Variant names:

• chr11-64713324-G-A
• rs370521049
• NM_015080.4:c.376C>T

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PM2 BP4_Strong BP7

The NM_015080.4(NRXN2):​c.376C>T​(p.Leu126Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000082 in 1,219,330 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 8.2e-7 (0 hom.)
• Consequence: NRXN2 NM_015080.4 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.56
• Publications: 0 publications found

Genes affected

NRXN2 (HGNC:8009): (neurexin 2) This gene encodes a member of the neurexin gene family. The products of these genes function as cell adhesion molecules and receptors in the vertebrate nervous system. These genes utilize two promoters. The majority of transcripts are produced from the upstream promoter and encode alpha-neurexin isoforms while a smaller number of transcripts are produced from the downstream promoter and encode beta-neuresin isoforms. The alpha-neurexins contain epidermal growth factor-like (EGF-like) sequences and laminin G domains, and have been shown to interact with neurexophilins. The beta-neurexins lack EGF-like sequences and contain fewer laminin G domains than alpha-neurexins. Alternative splicing and the use of alternative promoters may generate thousands of transcript variants (PMID: 12036300, PMID: 11944992).[provided by RefSeq, Jun 2010]

NRXN2 Gene-Disease associations (from GenCC):

• autism

  Inheritance: AD Classification: STRONG, LIMITED Submitted by: G2P, Ambry Genetics
• neurodevelopmental disorder

  Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Likely_benign. The variant received -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.51).
• BP7: Synonymous conserved (PhyloP=2.56 with no splicing effect.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_015080.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NRXN2	NM_015080.4	MANE Select	c.376C>T	p.Leu126Leu	synonymous	Exon 2 of 23	NP_055895.1
	NRXN2	NM_138732.3		c.376C>T	p.Leu126Leu	synonymous	Exon 2 of 20	NP_620060.1
	NRXN2	NM_001376262.1		c.376C>T	p.Leu126Leu	synonymous	Exon 2 of 23	NP_001363191.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NRXN2	ENST00000265459.11	TSL:5 MANE Select	c.376C>T	p.Leu126Leu	synonymous	Exon 2 of 23	ENSP00000265459.5
	NRXN2	ENST00000704782.1		c.376C>T	p.Leu126Leu	synonymous	Exon 1 of 22	ENSP00000516031.1
	NRXN2	ENST00000377559.7	TSL:1	c.376C>T	p.Leu126Leu	synonymous	Exon 2 of 20	ENSP00000366782.3

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome AF: 8.20e-7 AC: 1 AN: 1219330 Hom.: 0 Cov.: 34 AF XY: 0.00 AC XY: 0 AN XY: 595274

African (AFR) AF: 0.00 AC: 0 AN: 24056

American (AMR) AF: 0.00 AC: 0 AN: 11438

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 17290

East Asian (EAS) AF: 0.00 AC: 0 AN: 26938

South Asian (SAS) AF: 0.0000184 AC: 1 AN: 54490

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 29468

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3540

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1002192

Other (OTH) AF: 0.00 AC: 0 AN: 49918

GnomAD4 genome Cov.: 34

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.51
CADD	Benign	12
DANN	Uncertain	0.98
PhyloP100		2.6
PromoterAI		-0.0012	Neutral

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: rs370521049; hg19: chr11-64480796;