rs2304016

Variant names:

• chr2-165311993-A-G
• rs2304016
• NM_001040142.2:c.971-32A>G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001040142.2(SCN2A):​c.971-32A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00512 in 1,537,156 control chromosomes in the GnomAD database, including 189 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). There are indicators that this mutation may affect the branch point..

• Frequency:
  • Genomes: 𝑓 0.0058 (20 hom., cov: 32)
  • Exomes 𝑓: 0.0050 (169 hom.)
• Consequence: SCN2A NM_001040142.2 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.63

Genes affected

SCN2A (HGNC:10588): (sodium voltage-gated channel alpha subunit 2) Voltage-gated sodium channels are transmembrane glycoprotein complexes composed of a large alpha subunit with four repeat domains, each of which is composed of six membrane-spanning segments, and one or more regulatory beta subunits. Voltage-gated sodium channels function in the generation and propagation of action potentials in neurons and muscle. This gene encodes one member of the sodium channel alpha subunit gene family. Allelic variants of this gene are associated with seizure disorders and autism spectrum disorder. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Nov 2016]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: This position, referring to a specific DNA site, is a probable branch point but rather VUS (scored 4 / 10). The score ranges from 0 to 10, with values ≤3 considered benign and >5 classified as pathogenic. Computational evidence support a benign effect (BayesDel_noAF=-0.76).
• BP6: Variant 2-165311993-A-G is Benign according to our data. Variant chr2-165311993-A-G is described in ClinVar as [Benign]. Clinvar id is 1257386.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-165311993-A-G is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0826 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SCN2A	NM_001040142.2	c.971-32A>G		intron_variant	Intron 7 of 26	ENST00000375437.7	NP_001035232.1
SCN2A	NM_001371246.1	c.971-32A>G		intron_variant	Intron 7 of 26	ENST00000631182.3	NP_001358175.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SCN2A	ENST00000375437.7	c.971-32A>G		intron_variant	Intron 7 of 26	5	NM_001040142.2	ENSP00000364586.2
SCN2A	ENST00000631182.3	c.971-32A>G		intron_variant	Intron 7 of 26	5	NM_001371246.1	ENSP00000486885.1
SCN2A	ENST00000283256.10	c.971-32A>G		intron_variant	Intron 7 of 26	1		ENSP00000283256.6
SCN2A	ENST00000424833.5	c.971-32A>G		intron_variant	Intron 7 of 10	1		ENSP00000406454.2

Frequencies

GnomAD3 genomes AF: 0.00584 AC: 888 AN: 152130 Hom.: 20 Cov.: 32

Gnomad AFR AF: 0.000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00891

Gnomad ASJ AF: 0.0118

Gnomad EAS AF: 0.0898

Gnomad SAS AF: 0.00704

Gnomad FIN AF: 0.00922

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00134

Gnomad OTH AF: 0.00528

GnomAD3 exomes AF: 0.0119 AC: 2907 AN: 244650 Hom.: 77 AF XY: 0.0108 AC XY: 1423 AN XY: 132278

Gnomad AFR exome AF: 0.000376

Gnomad AMR exome AF: 0.0184

Gnomad ASJ exome AF: 0.00925

Gnomad EAS exome AF: 0.0897

Gnomad SAS exome AF: 0.00470

Gnomad FIN exome AF: 0.00816

Gnomad NFE exome AF: 0.00200

Gnomad OTH exome AF: 0.00653

GnomAD4 exome AF: 0.00505 AC: 6990 AN: 1384906 Hom.: 169 Cov.: 21 AF XY: 0.00505 AC XY: 3501 AN XY: 693192

Gnomad4 AFR exome AF: 0.000219

Gnomad4 AMR exome AF: 0.0180

Gnomad4 ASJ exome AF: 0.00959

Gnomad4 EAS exome AF: 0.0884

Gnomad4 SAS exome AF: 0.00441

Gnomad4 FIN exome AF: 0.00744

Gnomad4 NFE exome AF: 0.00131

Gnomad4 OTH exome AF: 0.00573

GnomAD4 genome AF: 0.00581 AC: 884 AN: 152250 Hom.: 20 Cov.: 32 AF XY: 0.00705 AC XY: 525 AN XY: 74446

Gnomad4 AFR AF: 0.000241

Gnomad4 AMR AF: 0.00890

Gnomad4 ASJ AF: 0.0118

Gnomad4 EAS AF: 0.0893

Gnomad4 SAS AF: 0.00684

Gnomad4 FIN AF: 0.00922

Gnomad4 NFE AF: 0.00134

Gnomad4 OTH AF: 0.00522

Alfa AF: 0.00235 Hom.: 1

Bravo AF: 0.00651

Asia WGS AF: 0.0430 AC: 149 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 28, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.76
CADD	Benign	15
DANN	Benign	0.84
La Branchor		0.80
BranchPoint Hunter		4.0

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.090		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: rs2304016; hg19: chr2-166168503;