rs141268327

Positions:

• chr2-166238128-T-C

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_001365536.1(SCN9A):​c.3767A>G​(p.Asn1256Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00723 in 1,611,512 control chromosomes in the GnomAD database, including 66 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 0.0049 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0075 (64 hom.)
• Consequence: SCN9A NM_001365536.1 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5 B:19
• Conservation: PhyloP100: 8.02

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]

SCN1A-AS1 (HGNC:54069): (SCN1A and SCN9A antisense RNA 1)

ACMG classification

Verdict is Benign. Variant got -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.015853316).
• BP6: Variant 2-166238128-T-C is Benign according to our data. Variant chr2-166238128-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 130265.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=9, Benign=6, Uncertain_significance=5}. Variant chr2-166238128-T-C is described in Lovd as [Likely_benign]. Variant chr2-166238128-T-C is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00492 (749/152334) while in subpopulation NFE AF= 0.00788 (536/68018). AF 95% confidence interval is 0.00733. There are 2 homozygotes in gnomad4. There are 332 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 2 SD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SCN9A	NM_001365536.1	c.3767A>G	p.Asn1256Ser	missense_variant	20/27	ENST00000642356.2	NP_001352465.1
SCN1A-AS1	NR_110260.1	n.612-10067T>C		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SCN9A	ENST00000642356.2	c.3767A>G	p.Asn1256Ser	missense_variant	20/27		NM_001365536.1	ENSP00000495601	P1
SCN1A-AS1	ENST00000651574.1	n.1290-10067T>C		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.00493 AC: 750 AN: 152216 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.00171

Gnomad AMI AF: 0.00548

Gnomad AMR AF: 0.00674

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00166

Gnomad FIN AF: 0.00122

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00789

Gnomad OTH AF: 0.00574

GnomAD3 exomes AF: 0.00449 AC: 1109 AN: 246844 Hom.: 5 AF XY: 0.00450 AC XY: 602 AN XY: 133674

Gnomad AFR exome AF: 0.00142

Gnomad AMR exome AF: 0.00424

Gnomad ASJ exome AF: 0.00130

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00106

Gnomad FIN exome AF: 0.00158

Gnomad NFE exome AF: 0.00751

Gnomad OTH exome AF: 0.00434

GnomAD4 exome AF: 0.00747 AC: 10897 AN: 1459178 Hom.: 64 Cov.: 29 AF XY: 0.00725 AC XY: 5262 AN XY: 725704

Gnomad4 AFR exome AF: 0.00138

Gnomad4 AMR exome AF: 0.00420

Gnomad4 ASJ exome AF: 0.000997

Gnomad4 EAS exome AF: 0.0000253

Gnomad4 SAS exome AF: 0.00100

Gnomad4 FIN exome AF: 0.00158

Gnomad4 NFE exome AF: 0.00912

Gnomad4 OTH exome AF: 0.00543

GnomAD4 genome AF: 0.00492 AC: 749 AN: 152334 Hom.: 2 Cov.: 32 AF XY: 0.00446 AC XY: 332 AN XY: 74494

Gnomad4 AFR AF: 0.00171

Gnomad4 AMR AF: 0.00673

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00166

Gnomad4 FIN AF: 0.00122

Gnomad4 NFE AF: 0.00788

Gnomad4 OTH AF: 0.00568

Alfa AF: 0.00686 Hom.: 8

Bravo AF: 0.00527

TwinsUK AF: 0.0138 AC: 51

ALSPAC AF: 0.00986 AC: 38

ESP6500AA AF: 0.00137 AC: 6

ESP6500EA AF: 0.00745 AC: 64

ExAC AF: 0.00417 AC: 506

Asia WGS AF: 0.00115 AC: 4 AN: 3476

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:5 Benign:19

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:8

Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Nov 07, 2016	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 13, 2020	This variant is associated with the following publications: (PMID: 28440294, 29934995, 23895530, 29911575, 29264398, 32707200) -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2024	SCN9A: BS2 -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 26, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jun 21, 2018	- -

not specified Benign:4

Likely benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Nov 11, 2014	- -
Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Sep 10, 2014	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

Primary erythromelalgia Uncertain:1 Benign:1

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Uncertain significance, criteria provided, single submitter	clinical testing	Genomic Research Center, Shahid Beheshti University of Medical Sciences	Aug 07, 2018	- -

Neuropathy, hereditary sensory and autonomic, type 2A Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Genomic Research Center, Shahid Beheshti University of Medical Sciences	Aug 07, 2018	- -
Likely benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -

Primary erythromelalgia;C1833661:Paroxysmal extreme pain disorder;C1855739:Channelopathy-associated congenital insensitivity to pain, autosomal recessive Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago

Mar 30, 2021

SCN9A NM_002977.3 exon 20 p.Asn1245Ser (c.3734A>G): This variant has been reported in the literature in 2 individuals with erythromelalgia (Zhang 2014 PMID:29911575, Haehner 2018 PMID:29934995). This variant was also seen in one individual with language impairment who also carried a second variant in SCN9A (Chen 2017 PMID:28440294). This variant is present in 0.7% (933/126946) of European alleles, including 2 homozygotes, in the Genome Aggregation Database (http://gnomad.broadinstitute.org/variant/2-167094638-T-C). This variant is present in ClinVar, with several labs classifying this variant as likely benign (Variation ID:130265). However, evolutionary conservation and computational predictive tools suggest that this variant may impact the protein. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain. -

Primary erythromelalgia;C0751122:Severe myoclonic epilepsy in infancy;C1833661:Paroxysmal extreme pain disorder;C1855739:Channelopathy-associated congenital insensitivity to pain, autosomal recessive;C2751778:Generalized epilepsy with febrile seizures plus, type 7 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago

Oct 22, 2018

SCN9A NM_002977.3 exon 20 p.Asn1245Ser (c.3734A>G): This variant has been reported in the literature in 2 individuals with erythromelalgia (Zhang 2014 PMID:29911575, Haehner 2018 PMID:29934995). This variant was also seen in one individual with language impairment who also carried a second variant in SCN9A (Chen 2017 PMID:28440294). This variant is present in 0.7% (933/126946) of European alleles, including 2 homozygotes, in the Genome Aggregation Database (http://gnomad.broadinstitute.org/variant/2-167094638-T-C). This variant is present in ClinVar, with several labs classifying this variant as likely benign (Variation ID:130265). However, evolutionary conservation and computational predictive tools suggest that this variant may impact the protein. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain. -

Severe myoclonic epilepsy in infancy Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genomic Research Center, Shahid Beheshti University of Medical Sciences

Aug 07, 2018

- -

Inherited Erythromelalgia Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Inborn genetic diseases Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 16, 2019

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. -

Channelopathy-associated congenital insensitivity to pain, autosomal recessive Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

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

Feb 01, 2024

- -

Paroxysmal extreme pain disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Uncertain	0.030
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.80	.;D;.;.;D;.
Eigen	Pathogenic	0.70
Eigen_PC	Pathogenic	0.70
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.94	D;.;D;D;D;D
M_CAP	Uncertain	0.28	D
MetaRNN	Benign	0.016	T;T;T;T;T;T
MetaSVM	Pathogenic	0.93	D
MutationAssessor	Benign	1.6	.;L;.;.;L;L
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.68	T
PROVEAN	Pathogenic	-4.8	D;.;.;.;.;D
REVEL	Pathogenic	0.90
Sift	Pathogenic	0.0	D;.;.;.;.;D
Sift4G	Benign	0.19	T;T;.;.;.;T
Vest4		0.69
MVP		0.91
MPC		0.50
ClinPred		0.031	T
GERP RS		5.3
Varity_R		0.82
gMVP		0.51

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs141268327; hg19: chr2-167094638; COSMIC: COSV104409259; COSMIC: COSV104409259;