rs758906955

chr2-165097377-T-C

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 1P and 12B. PP2 BP4_Moderate BP6_Moderate BS1 BS2

The NM_006922.4(SCN3A):c.4114A>G(p.Met1372Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000124 in 1,613,954 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.000033 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000010 (0 hom.)
• Consequence: SCN3A NM_006922.4 missense
• Clinical Significance: Likely benign criteria provided, single submitter P:1 B:1
• Conservation: PhyloP100: 0.602

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]

(HGNC:):

ACMG classification

Verdict is Benign. Variant got -11 ACMG points.

• PP2: Missense variant where missense usually causes diseases, SCN3A
• BP4: Computational evidence support a benign effect (MetaRNN=0.13425308).
• BP6: Variant 2-165097377-T-C is Benign according to our data. Variant chr2-165097377-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 522565.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.0000329 (5/152108) while in subpopulation AMR AF= 0.000196 (3/15268). AF 95% confidence interval is 0.0000529. There are 0 homozygotes in gnomad4. There are 4 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd at 5 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SCN3A	NM_006922.4	c.4114A>G	p.Met1372Val	missense_variant	23/28	ENST00000283254.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SCN3A	ENST00000283254.12	c.4114A>G	p.Met1372Val	missense_variant	23/28	1	NM_006922.4	P1

Frequencies

GnomAD3 genomes AF: 0.0000329 AC: 5 AN: 152108 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

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: 0.0000147

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.0000239 AC: 6 AN: 251398 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135868

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000173

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000103 AC: 15 AN: 1461846 Hom.: 0 Cov.: 31 AF XY: 0.00000413 AC XY: 3 AN XY: 727224

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000157

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000270

Gnomad4 OTH exome AF: 0.0000828

GnomAD4 genome AF: 0.0000329 AC: 5 AN: 152108 Hom.: 0 Cov.: 32 AF XY: 0.0000538 AC XY: 4 AN XY: 74298

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.000196

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.000478

Alfa AF: 0.0000278 Hom.: 0

Bravo AF: 0.0000491

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Likely benign

Submissions summary: Pathogenic:1 Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Epilepsy, familial focal, with variable foci 4 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Sep 01, 2020

- -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 15, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.067
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.30
Cadd	Benign	20
Dann	Benign	0.77
DEOGEN2	Uncertain	0.73	D;.;.;.;.
Eigen	Benign	-0.73
Eigen_PC	Benign	-0.53
FATHMM_MKL	Benign	0.15	N
LIST_S2	Uncertain	0.89	D;D;D;D;D
M_CAP	Benign	0.048	D
MetaRNN	Benign	0.13	T;T;T;T;T
MetaSVM	Benign	-0.34	T
MutationAssessor	Benign	-0.56	N;N;.;.;.
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.41	T
PROVEAN	Benign	-1.7	N;N;.;N;N
REVEL	Pathogenic	0.70
Sift	Benign	0.14	T;T;.;T;T
Sift4G	Benign	0.60	T;T;.;T;T
Polyphen		0.0040	B;B;.;B;B
Vest4		0.15
MutPred		0.49		Gain of loop (P = 0.0195);Gain of loop (P = 0.0195);.;.;.;
MVP		0.39
MPC		0.68
ClinPred		0.043	T
GERP RS		4.6
Varity_R		0.18
gMVP		0.85

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs758906955; hg19: chr2-165953887;