chr2-166272699-C-G

Position:

chr2-166272699-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP6

The NM_001365536.1(SCN9A):c.3051G>C(p.Lys1017Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000274 in 1,596,900 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0014 ( 1 hom., cov: 31)

Exomes 𝑓: 0.00015 ( 0 hom. )

Consequence

SCN9A
NM_001365536.1 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:3

Conservation

PhyloP100: 0.0990

Variant links:

Genes affected

SCN9A (HGNC:10597): (sodium voltage-gated channel alpha subunit 9) This gene encodes a voltage-gated sodium channel which plays a significant role in nociception signaling. Mutations in this gene have been associated with primary erythermalgia, channelopathy-associated insensitivity to pain, and paroxysmal extreme pain disorder. [provided by RefSeq, Aug 2009]

SCN9A links:

SCN1A-AS1 (HGNC:):

SCN1A-AS1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP6

Variant 2-166272699-C-G is Benign according to our data. Variant chr2-166272699-C-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 246380.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=2, Benign=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SCN9A	NM_001365536.1 linkuse as main transcript	c.3051G>C	p.Lys1017Asn	missense_variant	17/27	ENST00000642356.2	NP_001352465.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
SCN9A	ENST00000642356.2 linkuse as main transcript	c.3051G>C	p.Lys1017Asn	missense_variant	17/27		NM_001365536.1	ENSP00000495601.1	Q15858-1
SCN9A	ENST00000303354.11 linkuse as main transcript	c.3051G>C	p.Lys1017Asn	missense_variant	17/27	5		ENSP00000304748.7	Q15858-1
SCN9A	ENST00000409672.5 linkuse as main transcript	c.3018G>C	p.Lys1006Asn	missense_variant	17/27	5		ENSP00000386306.1	Q15858-3
SCN9A	ENST00000645907.1 linkuse as main transcript	c.3018G>C	p.Lys1006Asn	missense_variant	17/27			ENSP00000495983.1	Q15858-4

Frequencies

GnomAD3 genomes

AF:

0.00137

AC:

208

AN:

151620

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00482

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000396

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:

0.00144

GnomAD3 exomes

AF:

0.000383

AC:

AN:

237294

Hom.:

AF XY:

0.000288

AC XY:

AN XY:

128628

show subpopulations

Gnomad AFR exome

AF:

0.00539

Gnomad AMR exome

AF:

0.000284

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:

0.000153

AC:

221

AN:

1445164

Hom.:

Cov.:

AF XY:

0.000133

AC XY:

AN XY:

716928

show subpopulations

Gnomad4 AFR exome

AF:

0.00538

Gnomad4 AMR exome

AF:

0.000333

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000240

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

9.06e-7

Gnomad4 OTH exome

AF:

0.000487

GnomAD4 genome

AF:

0.00143

AC:

217

AN:

151736

Hom.:

Cov.:

AF XY:

0.00138

AC XY:

102

AN XY:

74110

show subpopulations

Gnomad4 AFR

AF:

0.00502

Gnomad4 AMR

AF:

0.000396

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00142

Alfa

AF:

0.000535

Hom.:

Bravo

AF:

0.00166

ESP6500AA

AF:

0.00471

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000480

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Apr 24, 2024	Reported as a variant of uncertain significance in a patient with epilepsy (PMID: 36539902); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; In silico analysis suggests this variant may impact gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown.; This variant is associated with the following publications: (PMID: 36539902) -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jul 28, 2017	- -

Inborn genetic diseases

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 07, 2021

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. -

Generalized epilepsy with febrile seizures plus, type 7;C2752089:Neuropathy, hereditary sensory and autonomic, type 2A

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 29, 2024

- -

SCN9A-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 12, 2019

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.17

BayesDel_addAF

Benign

-0.35

BayesDel_noAF

Benign

-0.28

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.52

.;D;.;.;D;.

Eigen

Benign

-0.64

Eigen_PC

Benign

-0.60

FATHMM_MKL

Uncertain

0.81

LIST_S2

Benign

0.66

T;.;T;T;T;T

M_CAP

Benign

0.084

MetaRNN

Benign

0.0079

T;T;T;T;T;T

MetaSVM

Uncertain

-0.065

MutationAssessor

Uncertain

2.4

.;M;.;.;M;M

PrimateAI

Benign

0.42

PROVEAN

Uncertain

-2.9

D;N;.;.;.;D

REVEL

Uncertain

0.30

Sift

Uncertain

0.023

D;D;.;.;.;D

Sift4G

Uncertain

0.048

D;T;.;.;.;T

Vest4

0.48

MutPred

0.46

Loss of methylation at K1006 (P = 0.0265);.;Loss of methylation at K1006 (P = 0.0265);Loss of methylation at K1006 (P = 0.0265);.;.;

MVP

0.44

MPC

0.57

ClinPred

0.079

GERP RS

2.6

Varity_R

0.35

gMVP

0.25

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.34

Details are displayed if max score is > 0.2

DS_AG_spliceai

0.34

Position offset: -7

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over