rs144906809

chr11-64651249-C-T

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_Moderate BP6_Moderate BS2

The NM_015080.4(NRXN2):c.2918+6G>A variant causes a splice donor region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00117 in 1,614,000 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0011 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0012 (7 hom.)
• Consequence: NRXN2 NM_015080.4 splice_donor_region, intron
• Scores: Splicing: ADA: 0.008299
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.318

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-AS1 (HGNC:40416): (NRXN2 antisense RNA 1)

ACMG classification

Verdict is Benign. Variant got -8 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.36).
• BP6: Variant 11-64651249-C-T is Benign according to our data. Variant chr11-64651249-C-T is described in ClinVar as [Benign]. Clinvar id is 211704.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr11-64651249-C-T is described in Lovd as [Benign].
• BS2: High AC in GnomAd at 171 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NRXN2	NM_015080.4	c.2918+6G>A		splice_donor_region_variant, intron_variant		ENST00000265459.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NRXN2	ENST00000265459.11	c.2918+6G>A		splice_donor_region_variant, intron_variant		5	NM_015080.4	P4
NRXN2-AS1	ENST00000433606.1	n.180+4671C>T		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes AF: 0.00112 AC: 171 AN: 152146 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000410

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000851

Gnomad ASJ AF: 0.0138

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.00116

Gnomad OTH AF: 0.00287

GnomAD3 exomes AF: 0.00139 AC: 349 AN: 250896 Hom.: 3 AF XY: 0.00138 AC XY: 187 AN XY: 135714

Gnomad AFR exome AF: 0.000677

Gnomad AMR exome AF: 0.00104

Gnomad ASJ exome AF: 0.0136

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000261

Gnomad FIN exome AF: 0.0000465

Gnomad NFE exome AF: 0.00118

Gnomad OTH exome AF: 0.00359

GnomAD4 exome AF: 0.00118 AC: 1722 AN: 1461736 Hom.: 7 Cov.: 31 AF XY: 0.00120 AC XY: 873 AN XY: 727176

Gnomad4 AFR exome AF: 0.00134

Gnomad4 AMR exome AF: 0.00107

Gnomad4 ASJ exome AF: 0.0130

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000301

Gnomad4 FIN exome AF: 0.0000375

Gnomad4 NFE exome AF: 0.000924

Gnomad4 OTH exome AF: 0.00252

GnomAD4 genome AF: 0.00112 AC: 171 AN: 152264 Hom.: 0 Cov.: 32 AF XY: 0.00105 AC XY: 78 AN XY: 74456

Gnomad4 AFR AF: 0.000409

Gnomad4 AMR AF: 0.000850

Gnomad4 ASJ AF: 0.0138

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000415

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00116

Gnomad4 OTH AF: 0.00284

Alfa AF: 0.00210 Hom.: 1

Bravo AF: 0.00143

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.00207

EpiControl AF: 0.00231

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Jun 25, 2019

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.36
Cadd	Benign	18
Dann	Benign	0.92

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0083
dbscSNV1_RF	Benign	0.17
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

Publications

LitVar

Other links and lift over

dbSNP: rs144906809; hg19: chr11-64418721;