11-64630393-G-C

Variant names:

• chr11-64630393-G-C
• rs376552947
• NM_015080.4:c.3757+9C>G

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_015080.4(NRXN2):​c.3757+9C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000277 in 1,444,258 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: 32)
  • Exomes 𝑓: 0.0000028 (0 hom.)
• Consequence: NRXN2 NM_015080.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.101
• 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: Ambry Genetics, G2P
• neurodevelopmental disorder

  Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics

ENSG00000309292 (HGNC:):

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).

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.3757+9C>G		intron	N/A	NP_055895.1	Q9P2S2-1
	NRXN2	NM_138732.3		c.3637+9C>G		intron	N/A	NP_620060.1	Q9P2S2-2
	NRXN2	NM_001376262.1		c.3757+9C>G		intron	N/A	NP_001363191.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NRXN2	ENST00000265459.11	TSL:5 MANE Select	c.3757+9C>G		intron	N/A	ENSP00000265459.5	Q9P2S2-1
	NRXN2	ENST00000704782.1		c.3766+9C>G		intron	N/A	ENSP00000516031.1	A0A994J5C3
	NRXN2	ENST00000377559.7	TSL:1	c.3637+9C>G		intron	N/A	ENSP00000366782.3	Q9P2S2-2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000412 AC: 1 AN: 242700 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000277 AC: 4 AN: 1444258 Hom.: 0 Cov.: 34 AF XY: 0.00000418 AC XY: 3 AN XY: 718470

African (AFR) AF: 0.00 AC: 0 AN: 32918

American (AMR) AF: 0.00 AC: 0 AN: 44234

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25424

East Asian (EAS) AF: 0.00 AC: 0 AN: 38876

South Asian (SAS) AF: 0.0000349 AC: 3 AN: 86024

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49594

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4880

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1103032

Other (OTH) AF: 0.0000169 AC: 1 AN: 59276

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	5.6
DANN	Benign	0.83
PhyloP100		-0.10

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs376552947; hg19: chr11-64397865;