rs140417984

chr2-165389563-C-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_001040142.2(SCN2A):c.5757C>T(p.Tyr1919=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000137 in 1,613,902 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00064 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000085 (2 hom.)
• Consequence: SCN2A NM_001040142.2 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.0980

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.48).
• BP6: Variant 2-165389563-C-T is Benign according to our data. Variant chr2-165389563-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 139021.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-165389563-C-T is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=0.098 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.000637 (97/152186) while in subpopulation AFR AF= 0.00219 (91/41532). AF 95% confidence interval is 0.00183. There are 0 homozygotes in gnomad4. There are 35 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd at 97 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SCN2A	NM_001040142.2	c.5757C>T	p.Tyr1919=	synonymous_variant	27/27	ENST00000375437.7
SCN2A	NM_001371246.1	c.5757C>T	p.Tyr1919=	synonymous_variant	27/27	ENST00000631182.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SCN2A	ENST00000375437.7	c.5757C>T	p.Tyr1919=	synonymous_variant	27/27	5	NM_001040142.2	P1
SCN2A	ENST00000631182.3	c.5757C>T	p.Tyr1919=	synonymous_variant	27/27	5	NM_001371246.1

Frequencies

GnomAD3 genomes AF: 0.000638 AC: 97 AN: 152068 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00220

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

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: 0.0000441

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000156 AC: 39 AN: 250592 Hom.: 0 AF XY: 0.0000960 AC XY: 13 AN XY: 135414

Gnomad AFR exome AF: 0.00209

Gnomad AMR exome AF: 0.0000869

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000884

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000848 AC: 124 AN: 1461716 Hom.: 2 Cov.: 33 AF XY: 0.0000853 AC XY: 62 AN XY: 727152

Gnomad4 AFR exome AF: 0.00296

Gnomad4 AMR exome AF: 0.0000671

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000348

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000360

Gnomad4 OTH exome AF: 0.000215

GnomAD4 genome AF: 0.000637 AC: 97 AN: 152186 Hom.: 0 Cov.: 32 AF XY: 0.000470 AC XY: 35 AN XY: 74398

Gnomad4 AFR AF: 0.00219

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000406 Hom.: 0

Bravo AF: 0.000756

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Jan 19, 2017	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 25, 2013	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Inborn genetic diseases Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 07, 2017

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Seizures, benign familial infantile, 3;C3150987:Developmental and epileptic encephalopathy, 11 Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 19, 2024

- -

SCN2A-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 26, 2019

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.48
Cadd	Benign	4.4
Dann	Benign	0.43

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

Publications

LitVar

Other links and lift over

dbSNP: rs140417984; hg19: chr2-166246073;