NM_001040142.2:c.-51-1735dupA

Variant names:

• chr2-165294010-T-TA
• rs67417831
• NM_001040142.2:c.-51-1735dupA

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BS1 BS2

The NM_001040142.2(SCN2A):​c.-51-1735dupA variant causes a intron change involving the alteration of a non-conserved nucleotide. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.017 (78 hom., cov: 0)
  • Exomes 𝑓: 0.040 (31 hom.)
• Consequence: SCN2A NM_001040142.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.292
• Publications: 0 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 Submitted by: ClinGen, Illumina
• developmental and epileptic encephalopathy, 11

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• 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: Labcorp Genetics (formerly Invitae), Ambry Genetics
• 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 -8 ACMG points.

• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.0165 (923/55914) while in subpopulation EAS AF = 0.0444 (67/1508). AF 95% confidence interval is 0.0359. There are 78 homozygotes in GnomAd4. There are 446 alleles in the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check.
• BS2: High AC in GnomAd4 at 923 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SCN2A	NM_001040142.2	c.-51-1735dupA		intron_variant	Intron 1 of 26	ENST00000375437.7	NP_001035232.1
SCN2A	NM_001371246.1	c.-51-1735dupA		intron_variant	Intron 1 of 26	ENST00000631182.3	NP_001358175.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SCN2A	ENST00000375437.7	c.-51-1763_-51-1762insA		intron_variant	Intron 1 of 26	5	NM_001040142.2	ENSP00000364586.2
SCN2A	ENST00000631182.3	c.-51-1763_-51-1762insA		intron_variant	Intron 1 of 26	5	NM_001371246.1	ENSP00000486885.1
SCN2A	ENST00000424833.5	c.-51-1763_-51-1762insA		intron_variant	Intron 1 of 10	1		ENSP00000406454.2
SCN2A	ENST00000283256.10	c.-177_-176insA		upstream_gene_variant		1		ENSP00000283256.6

Frequencies

GnomAD3 genomes AF: 0.0165 AC: 923 AN: 55904 Hom.: 78 Cov.: 0

Gnomad AFR AF: 0.0380

Gnomad AMI AF: 0.0476

Gnomad AMR AF: 0.0128

Gnomad ASJ AF: 0.00757

Gnomad EAS AF: 0.0444

Gnomad SAS AF: 0.0128

Gnomad FIN AF: 0.0168

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00701

Gnomad OTH AF: 0.0142

GnomAD4 exome AF: 0.0398 AC: 3776 AN: 94876 Hom.: 31 Cov.: 0 AF XY: 0.0404 AC XY: 1837 AN XY: 45526

African (AFR) AF: 0.0282 AC: 76 AN: 2698

American (AMR) AF: 0.0250 AC: 4 AN: 160

Ashkenazi Jewish (ASJ) AF: 0.0282 AC: 21 AN: 746

East Asian (EAS) AF: 0.0383 AC: 17 AN: 444

South Asian (SAS) AF: 0.0422 AC: 91 AN: 2156

European-Finnish (FIN) AF: 0.0476 AC: 2 AN: 42

Middle Eastern (MID) AF: 0.0126 AC: 3 AN: 238

European-Non Finnish (NFE) AF: 0.0404 AC: 3429 AN: 84978

Other (OTH) AF: 0.0390 AC: 133 AN: 3414

GnomAD4 genome AF: 0.0165 AC: 923 AN: 55914 Hom.: 78 Cov.: 0 AF XY: 0.0183 AC XY: 446 AN XY: 24332

African (AFR) AF: 0.0380 AC: 517 AN: 13608

American (AMR) AF: 0.0128 AC: 43 AN: 3360

Ashkenazi Jewish (ASJ) AF: 0.00757 AC: 15 AN: 1982

East Asian (EAS) AF: 0.0444 AC: 67 AN: 1508

South Asian (SAS) AF: 0.0128 AC: 11 AN: 862

European-Finnish (FIN) AF: 0.0168 AC: 5 AN: 298

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 46

European-Non Finnish (NFE) AF: 0.00701 AC: 232 AN: 33112

Other (OTH) AF: 0.0142 AC: 9 AN: 634

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.29
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs67417831; hg19: chr2-166150520; COSMIC: COSV51851512; COSMIC: COSV51851512;