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GeneBe

2-166238220-G-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BS1BS2

The NM_001365536.1(SCN9A):c.3675C>A(p.Ile1225=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00154 in 1,600,150 control chromosomes in the GnomAD database, including 52 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0021 ( 4 hom., cov: 32)
Exomes 𝑓: 0.0015 ( 48 hom. )

Consequence

SCN9A
NM_001365536.1 synonymous

Scores

2

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:11

Conservation

PhyloP100: -0.750
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]
SCN1A-AS1 (HGNC:54069): (SCN1A and SCN9A antisense RNA 1)

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -19 ACMG points.

BP4
?
    BP4 - Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc.)
Computational evidence support a benign effect (BayesDel_noAF=-0.45).
BP6
?
    BP6 - Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation
Variant 2-166238220-G-T is Benign according to our data. Variant chr2-166238220-G-T is described in ClinVar as [Benign]. Clinvar id is 130264.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-166238220-G-T is described in Lovd as [Benign].
BP7
?
    BP7 - A synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved
Synonymous conserved (PhyloP=-0.75 with no splicing effect.
BS1
?
    BS1 - Allele frequency is greater than expected for disorder
Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.00207 (315/152046) while in subpopulation EAS AF= 0.0505 (261/5164). AF 95% confidence interval is 0.0455. There are 4 homozygotes in gnomad4. There are 175 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
BS2
?
    BS2 - Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age
High Homozygotes in GnomAd at 4 SD gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
SCN9ANM_001365536.1 linkuse as main transcriptc.3675C>A p.Ile1225= synonymous_variant 20/27 ENST00000642356.2
SCN1A-AS1NR_110260.1 linkuse as main transcriptn.612-9975G>T intron_variant, non_coding_transcript_variant

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
SCN9AENST00000642356.2 linkuse as main transcriptc.3675C>A p.Ile1225= synonymous_variant 20/27 NM_001365536.1 P1Q15858-1
SCN1A-AS1ENST00000651574.1 linkuse as main transcriptn.1290-9975G>T intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes
?
    Genome Aggregation Database, over 76,156 genomes
AF:
0.00208
AC:
316
AN:
151928
Hom.:
4
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.000242
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000131
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.0508
Gnomad SAS
AF:
0.00457
Gnomad FIN
AF:
0.000378
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.000177
Gnomad OTH
AF:
0.00144
GnomAD3 exomes
AF:
0.00426
AC:
996
AN:
233756
Hom.:
22
AF XY:
0.00413
AC XY:
522
AN XY:
126290
show subpopulations
Gnomad AFR exome
AF:
0.000341
Gnomad AMR exome
AF:
0.0000941
Gnomad ASJ exome
AF:
0.000514
Gnomad EAS exome
AF:
0.0501
Gnomad SAS exome
AF:
0.00178
Gnomad FIN exome
AF:
0.000898
Gnomad NFE exome
AF:
0.000312
Gnomad OTH exome
AF:
0.00262
GnomAD4 exome
AF:
0.00148
AC:
2144
AN:
1448104
Hom.:
48
Cov.:
28
AF XY:
0.00148
AC XY:
1064
AN XY:
719562
show subpopulations
Gnomad4 AFR exome
AF:
0.000181
Gnomad4 AMR exome
AF:
0.0000928
Gnomad4 ASJ exome
AF:
0.000425
Gnomad4 EAS exome
AF:
0.0406
Gnomad4 SAS exome
AF:
0.00179
Gnomad4 FIN exome
AF:
0.000829
Gnomad4 NFE exome
AF:
0.000102
Gnomad4 OTH exome
AF:
0.00359
GnomAD4 genome
?
    Genome Aggregation Database, over 76,156 genomes
AF:
0.00207
AC:
315
AN:
152046
Hom.:
4
Cov.:
32
AF XY:
0.00235
AC XY:
175
AN XY:
74314
show subpopulations
Gnomad4 AFR
AF:
0.000241
Gnomad4 AMR
AF:
0.000131
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.0505
Gnomad4 SAS
AF:
0.00499
Gnomad4 FIN
AF:
0.000378
Gnomad4 NFE
AF:
0.000177
Gnomad4 OTH
AF:
0.000949
Alfa
AF:
0.000260
Hom.:
0
Bravo
AF:
0.00244
Asia WGS
AF:
0.0270
AC:
93
AN:
3478

ClinVar

Significance: Benign
Submissions summary: Benign:11
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not specified Benign:5
Benign, no assertion criteria providedclinical testingClinical Genetics, Academic Medical Center-- -
Benign, criteria provided, single submitterclinical testingPreventionGenetics, part of Exact Sciences-- -
Benign, criteria provided, single submitterclinical testingEurofins Ntd Llc (ga)Mar 19, 2015- -
Likely benign, no assertion criteria providedclinical testingGenetic Services Laboratory, University of Chicago-Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -
Benign, no assertion criteria providedclinical testingJoint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+-- -
Primary erythromelalgia Benign:1
Benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaJan 13, 2018This 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. -
Channelopathy-associated congenital insensitivity to pain, autosomal recessive Benign:1
Benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaJan 13, 2018This 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. -
Generalized epilepsy with febrile seizures plus, type 7;C2752089:Neuropathy, hereditary sensory and autonomic, type 2A Benign:1
Benign, criteria provided, single submitterclinical testingInvitaeJan 31, 2024- -
not provided Benign:1
Benign, criteria provided, single submitterclinical testingGeneDxMar 03, 2015- -
Small fiber neuropathy Benign:1
Benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaJun 14, 2016- -
Paroxysmal extreme pain disorder Benign:1
Benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaJan 13, 2018This 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
BayesDel_noAF
Benign
-0.45
Cadd
Benign
3.7
Dann
Benign
0.75
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7

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

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

Other links and lift over

dbSNP: rs77144869; hg19: chr2-167094730; COSMIC: COSV57611133; COSMIC: COSV57611133; API