rs377164316

chr11-64607488-C-A

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_015080.4(NRXN2):c.4847G>T(p.Gly1616Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000534 in 1,603,352 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.00028 (0 hom., cov: 30)
  • Exomes 𝑓: 0.00056 (1 hom.)
• Consequence: NRXN2 NM_015080.4 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.56

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]

ACMG classification

Verdict is Benign. Variant got -10 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.029367626).
• BP6: Variant 11-64607488-C-A is Benign according to our data. Variant chr11-64607488-C-A is described in ClinVar as [Likely_benign]. Clinvar id is 436043.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High AC in GnomAd at 42 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NRXN2	NM_015080.4	c.4847G>T	p.Gly1616Val	missense_variant	23/23	ENST00000265459.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NRXN2	ENST00000265459.11	c.4847G>T	p.Gly1616Val	missense_variant	23/23	5	NM_015080.4	P4

Frequencies

GnomAD3 genomes AF: 0.000276 AC: 42 AN: 152000 Hom.: 0 Cov.: 30

Gnomad AFR AF: 0.000145

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000515

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000154 AC: 35 AN: 227586 Hom.: 0 AF XY: 0.000159 AC XY: 20 AN XY: 125784

Gnomad AFR exome AF: 0.000370

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000299

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000561 AC: 814 AN: 1451234 Hom.: 1 Cov.: 33 AF XY: 0.000549 AC XY: 396 AN XY: 721424

Gnomad4 AFR exome AF: 0.0000599

Gnomad4 AMR exome AF: 0.0000225

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000712

Gnomad4 OTH exome AF: 0.000350

GnomAD4 genome AF: 0.000276 AC: 42 AN: 152118 Hom.: 0 Cov.: 30 AF XY: 0.000255 AC XY: 19 AN XY: 74368

Gnomad4 AFR AF: 0.000145

Gnomad4 AMR AF: 0.0000653

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000515

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000475 Hom.: 0

Bravo AF: 0.000246

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000778 AC: 3

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000471 AC: 4

ExAC AF: 0.000134 AC: 16

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

May 31, 2016

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.094
BayesDel_addAF	Benign	-0.33	T
BayesDel_noAF	Benign	-0.39
Cadd	Uncertain	26
Dann	Benign	0.94
DEOGEN2	Benign	0.25	T;T;.;T;.
Eigen	Benign	-0.21
Eigen_PC	Benign	-0.083
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Uncertain	0.89	D;.;D;D;D
M_CAP	Uncertain	0.12	D
MetaRNN	Benign	0.029	T;T;T;T;T
MetaSVM	Benign	-0.98	T
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Pathogenic	0.87	D
PROVEAN	Uncertain	-2.6	D;D;D;D;D
REVEL	Benign	0.11
Sift	Benign	0.28	T;T;T;T;T
Sift4G	Benign	0.29	T;T;T;T;T
Polyphen		0.078	B;P;P;P;.
Vest4		0.31
MVP		0.068
MPC		1.4
ClinPred		0.048	T
GERP RS		3.8
Varity_R		0.40
gMVP		0.60

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.12		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: rs377164316; hg19: chr11-64374960;