3-38697386-T-C

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_006514.4(SCN10A):c.5834A>G(p.Glu1945Gly) variant causes a missense change. The variant allele was found at a frequency of 0.00043 in 1,614,182 control chromosomes in the GnomAD database, including 8 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00021 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00045 (8 hom.)
• Consequence: SCN10A NM_006514.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 4.92

Genes affected

SCN10A (HGNC:10582): (sodium voltage-gated channel alpha subunit 10) The protein encoded by this gene is a tetrodotoxin-resistant voltage-gated sodium channel alpha subunit. The properties of the channel formed by the encoded transmembrane protein can be altered by interaction with different beta subunits. This protein may be involved in the onset of pain associated with peripheral neuropathy. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jun 2014]

ACMG classification

Verdict is Benign. Variant got -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0046025217).
• BP6: Variant 3-38697386-T-C is Benign according to our data. Variant chr3-38697386-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 391439.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-38697386-T-C is described in Lovd as [Likely_benign].
• BS2: High AC in GnomAd at 32 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SCN10A	NM_006514.4	c.5834A>G	p.Glu1945Gly	missense_variant	28/28	ENST00000449082.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SCN10A	ENST00000449082.3	c.5834A>G	p.Glu1945Gly	missense_variant	28/28	1	NM_006514.4	P4
SCN10A	ENST00000655275.1	c.5858A>G	p.Glu1953Gly	missense_variant	28/28
SCN10A	ENST00000643924.1	c.5831A>G	p.Glu1944Gly	missense_variant	27/27			A1

Frequencies

GnomAD3 genomes AF: 0.000210 AC: 32 AN: 152208 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000482

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00621

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000904 AC: 227 AN: 251208 Hom.: 2 AF XY: 0.00136 AC XY: 184 AN XY: 135746

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00725

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000653

GnomAD4 exome AF: 0.000453 AC: 662 AN: 1461856 Hom.: 8 Cov.: 32 AF XY: 0.000677 AC XY: 492 AN XY: 727230

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00740

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000270

Gnomad4 OTH exome AF: 0.000298

GnomAD4 genome AF: 0.000210 AC: 32 AN: 152326 Hom.: 0 Cov.: 32 AF XY: 0.000322 AC XY: 24 AN XY: 74486

Gnomad4 AFR AF: 0.0000481

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00622

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000529

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00101 AC: 123

Asia WGS AF: 0.00520 AC: 18 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Dec 01, 2016

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. -

Brugada syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Dec 08, 2023

- -

Cardiovascular phenotype Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 06, 2022

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.090
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.15
Cadd	Benign	21
Dann	Uncertain	0.99
DEOGEN2	Benign	0.10	T;.;T;.
Eigen	Benign	-0.53
Eigen_PC	Benign	-0.43
FATHMM_MKL	Benign	0.24	N
M_CAP	Benign	0.037	D
MetaRNN	Benign	0.0046	T;T;T;T
MetaSVM	Uncertain	-0.25	T
MutationAssessor	Benign	0.0	N;.;N;.
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-2.0	N;.;.;.
REVEL	Uncertain	0.30
Sift	Benign	0.074	T;.;.;.
Sift4G	Benign	0.23	T;.;.;.
Polyphen		0.32	B;.;B;.
Vest4		0.082
MVP		0.90
MPC		0.081
ClinPred		0.042	T
GERP RS		5.4
Varity_R		0.11
gMVP		0.53

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: rs372702302; hg19: chr3-38738877;