11-64713505-C-T

Variant names:

• chr11-64713505-C-T
• NM_015080.4:c.195G>A
• NRXN2 p.Leu65Leu

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 2P and 3B. PM2 BP4_Moderate BP7

The NM_015080.4(NRXN2):​c.195G>A​(p.Leu65Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. L65L) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: NRXN2 NM_015080.4 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.98
• 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 -1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.46).
• BP7: Synonymous conserved (PhyloP=2.98 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NRXN2	NM_015080.4	MANE Select	c.195G>A	p.Leu65Leu	synonymous	Exon 2 of 23	NP_055895.1	Q9P2S2-1
	NRXN2	NM_138732.3		c.195G>A	p.Leu65Leu	synonymous	Exon 2 of 20	NP_620060.1	Q9P2S2-2
	NRXN2	NM_001376262.1		c.195G>A	p.Leu65Leu	synonymous	Exon 2 of 23	NP_001363191.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NRXN2	ENST00000265459.11	TSL:5 MANE Select	c.195G>A	p.Leu65Leu	synonymous	Exon 2 of 23	ENSP00000265459.5	Q9P2S2-1
	NRXN2	ENST00000704782.1		c.195G>A	p.Leu65Leu	synonymous	Exon 1 of 22	ENSP00000516031.1	A0A994J5C3
	NRXN2	ENST00000377559.7	TSL:1	c.195G>A	p.Leu65Leu	synonymous	Exon 2 of 20	ENSP00000366782.3	Q9P2S2-2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1367770 Hom.: 0 Cov.: 34 AF XY: 0.00 AC XY: 0 AN XY: 677454

African (AFR) AF: 0.00 AC: 0 AN: 28770

American (AMR) AF: 0.00 AC: 0 AN: 34784

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23936

East Asian (EAS) AF: 0.00 AC: 0 AN: 32528

South Asian (SAS) AF: 0.00 AC: 0 AN: 77420

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 34680

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4318

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1074698

Other (OTH) AF: 0.00 AC: 0 AN: 56636

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.46
CADD	Benign	12
DANN	Uncertain	0.98
PhyloP100		3.0
PromoterAI		-0.020	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

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

Other links and lift over

hg19: chr11-64480977;