rs145171998

Variant names:

• chr2-165170450-A-G
• rs145171998
• NM_006922.4:c.363T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Moderate BP6 BP7 BS1 BS2

The NM_006922.4(SCN3A):​c.363T>C​(p.Ala121Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000158 in 1,605,088 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 Conflicting classifications of pathogenicity (no stars). The gene SCN3A is included in the ClinGen Criteria Specification Registry.

• Frequency:
  • Genomes: 𝑓 0.00018 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00016 (2 hom.)
• Consequence: SCN3A NM_006922.4 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:2
• Conservation: PhyloP100: 3.12
• Publications: 0 publications found

Genes affected

SCN3A (HGNC:10590): (sodium voltage-gated channel alpha subunit 3) Voltage-gated sodium channels are transmembrane glycoprotein complexes composed of a large alpha subunit with 24 transmembrane domains and one or more regulatory beta subunits. They are responsible for the generation and propagation of action potentials in neurons and muscle. This gene encodes one member of the sodium channel alpha subunit gene family, and is found in a cluster of five alpha subunit genes on chromosome 2. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

SCN3A Gene-Disease associations (from GenCC):

• genetic developmental and epileptic encephalopathy

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Illumina, ClinGen, PanelApp Australia
• developmental and epileptic encephalopathy, 62

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• epilepsy, familial focal, with variable foci 4

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
• undetermined early-onset epileptic encephalopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000236283 (HGNC:):

ACMG classification

Specifications for SCN3A are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.45).
• BP6: Variant 2-165170450-A-G is Benign according to our data. Variant chr2-165170450-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 240710.
• BP7: Synonymous conserved (PhyloP=3.12 with no splicing effect.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.000178 (27/152110) while in subpopulation AMR AF = 0.00177 (27/15258). AF 95% confidence interval is 0.00125. There are 0 homozygotes in GnomAd4. There are 18 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 27 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006922.4. 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
	SCN3A	NM_006922.4	MANE Select	c.363T>C	p.Ala121Ala	synonymous	Exon 4 of 28	NP_008853.3
	SCN3A	NM_001081676.2		c.363T>C	p.Ala121Ala	synonymous	Exon 4 of 28	NP_001075145.1	Q9NY46-4
	SCN3A	NM_001081677.2		c.363T>C	p.Ala121Ala	synonymous	Exon 4 of 28	NP_001075146.1	Q9NY46-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SCN3A	ENST00000283254.12	TSL:1 MANE Select	c.363T>C	p.Ala121Ala	synonymous	Exon 4 of 28	ENSP00000283254.7	Q9NY46-3
	SCN3A	ENST00000409101.7	TSL:1	c.363T>C	p.Ala121Ala	synonymous	Exon 4 of 28	ENSP00000386726.3	Q9NY46-2
	SCN3A	ENST00000706067.1		c.363T>C	p.Ala121Ala	synonymous	Exon 4 of 28	ENSP00000516211.1	A0A994J5P2

Frequencies

GnomAD3 genomes AF: 0.000178 AC: 27 AN: 151992 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00177

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: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000811 AC: 203 AN: 250234 AF XY: 0.000665

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00578

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000657

GnomAD4 exome AF: 0.000156 AC: 227 AN: 1452978 Hom.: 2 Cov.: 29 AF XY: 0.000138 AC XY: 100 AN XY: 723382

African (AFR) AF: 0.00 AC: 0 AN: 33232

American (AMR) AF: 0.00494 AC: 220 AN: 44566

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25992

East Asian (EAS) AF: 0.00 AC: 0 AN: 39488

South Asian (SAS) AF: 0.00 AC: 0 AN: 86020

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53358

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5726

European-Non Finnish (NFE) AF: 0.00000181 AC: 2 AN: 1104548

Other (OTH) AF: 0.0000833 AC: 5 AN: 60048

GnomAD4 genome AF: 0.000178 AC: 27 AN: 152110 Hom.: 0 Cov.: 32 AF XY: 0.000242 AC XY: 18 AN XY: 74374

African (AFR) AF: 0.00 AC: 0 AN: 41566

American (AMR) AF: 0.00177 AC: 27 AN: 15258

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67854

Other (OTH) AF: 0.00 AC: 0 AN: 2112

Alfa AF: 0.000217 Hom.: 0

Bravo AF: 0.000438

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	1	not provided (2)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.45
CADD	Benign	11
DANN	Benign	0.86
PhyloP100		3.1
Mutation Taster		=84/16	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: rs145171998; hg19: chr2-166026960;