Variant rs141268327 details in Genebe, Genetics Data Aggregator

ACMG classification

Classification made for transcript

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: {Uncertain_significance=5, Benign=5, Likely_benign=10}. 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 rank	MANE	Protein	UniProt
SCN9A	NM_001365536.1 link	c.3767A>G	p.Asn1256Ser	missense_variant	Exon 20 of 27	ENST00000642356.2	NP_001352465.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
SCN9A	ENST00000642356.2 link	c.3767A>G	p.Asn1256Ser	missense_variant	Exon 20 of 27		NM_001365536.1	ENSP00000495601.1	Q15858-1
SCN9A	ENST00000303354.11 link	c.3767A>G	p.Asn1256Ser	missense_variant	Exon 20 of 27	5		ENSP00000304748.7	Q15858-1
SCN9A	ENST00000409672.5 link	c.3734A>G	p.Asn1245Ser	missense_variant	Exon 20 of 27	5		ENSP00000386306.1	Q15858-3
SCN9A	ENST00000645907.1 link	c.3734A>G	p.Asn1245Ser	missense_variant	Exon 20 of 27			ENSP00000495983.1	Q15858-4

Frequencies

GnomAD3 genomes

AF:

0.00493

AC:

750

AN:

152216

Hom.:

2

Cov.:

32

show subpopulations

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

show subpopulations

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

show subpopulations

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

show subpopulations

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:5Benign:19

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Benign:7

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	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Sep 30, 2024	- -
Likely benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
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, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2025	SCN9A: BS2 -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

not specified

Benign:5

Likely benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Sep 10, 2014	- -
Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Nov 11, 2014	- -
Likely benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Sep 30, 2024	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

Primary erythromelalgia

Uncertain:1Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Genomic Research Center, Shahid Beheshti University of Medical Sciences	Aug 07, 2018	- -
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. -

Neuropathy, hereditary sensory and autonomic, type 2A

Uncertain:1Benign: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 03, 2025

- -

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

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

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

rs141268327

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