chr2-165313617-T-C

Variant names:

• chr2-165313617-T-C
• rs2121371
• NM_001040142.2:c.1035-3T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001040142.2(SCN2A):​c.1035-3T>C variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.823 in 1,612,776 control chromosomes in the GnomAD database, including 548,643 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.82 (50729 hom., cov: 31)
  • Exomes 𝑓: 0.82 (497914 hom.)
• Consequence: SCN2A NM_001040142.2 splice_region, intron
• Scores: Splicing: ADA: 0.0001398
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:14
• Conservation: PhyloP100: 0.188
• Publications: 18 publications found

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]

SCN2A Gene-Disease associations (from GenCC):

• complex neurodevelopmental disorder

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Illumina, ClinGen, PanelApp Australia
• developmental and epileptic encephalopathy, 11

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics
• intellectual disability

  Inheritance: AD Classification: DEFINITIVE Submitted by: G2P
• episodic ataxia, type 9

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• seizures, benign familial infantile, 3

  Inheritance: AD Classification: STRONG Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• benign familial infantile epilepsy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• benign familial neonatal-infantile seizures

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Dravet syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• genetic developmental and epileptic encephalopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• infantile spasms

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• malignant migrating partial seizures of infancy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.5).
• BP6: Variant 2-165313617-T-C is Benign according to our data. Variant chr2-165313617-T-C is described in ClinVar as Benign. ClinVar VariationId is 130216.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.834 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001040142.2. 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
	SCN2A	NM_001040142.2	MANE Select	c.1035-3T>C		splice_region intron	N/A	NP_001035232.1	Q99250-1
	SCN2A	NM_001371246.1	MANE Plus Clinical	c.1035-3T>C		splice_region intron	N/A	NP_001358175.1	Q99250-2
	SCN2A	NM_001040143.2		c.1035-3T>C		splice_region intron	N/A	NP_001035233.1	Q99250-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SCN2A	ENST00000375437.7	TSL:5 MANE Select	c.1035-3T>C		splice_region intron	N/A	ENSP00000364586.2	Q99250-1
	SCN2A	ENST00000631182.3	TSL:5 MANE Plus Clinical	c.1035-3T>C		splice_region intron	N/A	ENSP00000486885.1	Q99250-2
	SCN2A	ENST00000283256.10	TSL:1	c.1035-3T>C		splice_region intron	N/A	ENSP00000283256.6	Q99250-1

Frequencies

GnomAD3 genomes AF: 0.816 AC: 123877 AN: 151870 Hom.: 50691 Cov.: 31

Gnomad AFR AF: 0.808

Gnomad AMI AF: 0.749

Gnomad AMR AF: 0.824

Gnomad ASJ AF: 0.781

Gnomad EAS AF: 0.749

Gnomad SAS AF: 0.732

Gnomad FIN AF: 0.769

Gnomad MID AF: 0.741

Gnomad NFE AF: 0.840

Gnomad OTH AF: 0.811

GnomAD2 exomes AF: 0.802 AC: 201564 AN: 251294 AF XY: 0.797

Gnomad AFR exome AF: 0.809

Gnomad AMR exome AF: 0.816

Gnomad ASJ exome AF: 0.780

Gnomad EAS exome AF: 0.780

Gnomad FIN exome AF: 0.767

Gnomad NFE exome AF: 0.835

Gnomad OTH exome AF: 0.778

GnomAD4 exome AF: 0.824 AC: 1203871 AN: 1460788 Hom.: 497914 Cov.: 50 AF XY: 0.820 AC XY: 595988 AN XY: 726718

African (AFR) AF: 0.799 AC: 26708 AN: 33438

American (AMR) AF: 0.811 AC: 36269 AN: 44700

Ashkenazi Jewish (ASJ) AF: 0.784 AC: 20453 AN: 26094

East Asian (EAS) AF: 0.684 AC: 27162 AN: 39682

South Asian (SAS) AF: 0.714 AC: 61590 AN: 86230

European-Finnish (FIN) AF: 0.764 AC: 40831 AN: 53410

Middle Eastern (MID) AF: 0.708 AC: 4074 AN: 5758

European-Non Finnish (NFE) AF: 0.844 AC: 938010 AN: 1111136

Other (OTH) AF: 0.808 AC: 48774 AN: 60340

GnomAD4 genome AF: 0.816 AC: 123967 AN: 151988 Hom.: 50729 Cov.: 31 AF XY: 0.811 AC XY: 60257 AN XY: 74270

African (AFR) AF: 0.808 AC: 33505 AN: 41462

American (AMR) AF: 0.824 AC: 12563 AN: 15254

Ashkenazi Jewish (ASJ) AF: 0.781 AC: 2713 AN: 3472

East Asian (EAS) AF: 0.749 AC: 3847 AN: 5136

South Asian (SAS) AF: 0.731 AC: 3516 AN: 4810

European-Finnish (FIN) AF: 0.769 AC: 8136 AN: 10576

Middle Eastern (MID) AF: 0.735 AC: 216 AN: 294

European-Non Finnish (NFE) AF: 0.840 AC: 57083 AN: 67972

Other (OTH) AF: 0.812 AC: 1708 AN: 2104

Alfa AF: 0.824 Hom.: 34019

Bravo AF: 0.820

Asia WGS AF: 0.739 AC: 2568 AN: 3478

EpiCase AF: 0.828

EpiControl AF: 0.834

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	-	3	not provided (3)
-	-	2	Seizures, benign familial infantile, 3 (2)
-	-	1	Developmental and epileptic encephalopathy, 11 (1)
-	-	1	Episodic ataxia, type 9 (1)
-	-	1	Inborn genetic diseases (1)
-	-	1	Seizures, benign familial infantile, 3;C3150987:Developmental and epileptic encephalopathy, 11 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.50
CADD	Benign	12
DANN	Benign	0.65
PhyloP100		0.19
Mutation Taster		=99/1	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00014
dbscSNV1_RF	Benign	0.010
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

Other links and lift over

dbSNP: rs2121371; hg19: chr2-166170127;