rs141268327
Variant summary
Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2
The NM_001365536.1(SCN9A):āc.3767A>Gā(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
Consequence
NM_001365536.1 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -13 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
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SCN9A | NM_001365536.1 | 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 | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
SCN9A | ENST00000642356.2 | c.3767A>G | p.Asn1256Ser | missense_variant | Exon 20 of 27 | NM_001365536.1 | ENSP00000495601.1 | |||
SCN9A | ENST00000303354.11 | c.3767A>G | p.Asn1256Ser | missense_variant | Exon 20 of 27 | 5 | ENSP00000304748.7 | |||
SCN9A | ENST00000409672.5 | c.3734A>G | p.Asn1245Ser | missense_variant | Exon 20 of 27 | 5 | ENSP00000386306.1 | |||
SCN9A | ENST00000645907.1 | c.3734A>G | p.Asn1245Ser | missense_variant | Exon 20 of 27 | ENSP00000495983.1 |
Frequencies
GnomAD3 genomes AF: 0.00493 AC: 750AN: 152216Hom.: 2 Cov.: 32
GnomAD3 exomes AF: 0.00449 AC: 1109AN: 246844Hom.: 5 AF XY: 0.00450 AC XY: 602AN XY: 133674
GnomAD4 exome AF: 0.00747 AC: 10897AN: 1459178Hom.: 64 Cov.: 29 AF XY: 0.00725 AC XY: 5262AN XY: 725704
GnomAD4 genome AF: 0.00492 AC: 749AN: 152334Hom.: 2 Cov.: 32 AF XY: 0.00446 AC XY: 332AN XY: 74494
ClinVar
Submissions by phenotype
not provided Benign:7
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This variant is associated with the following publications: (PMID: 28440294, 29934995, 23895530, 29911575, 29264398, 32707200) -
SCN9A: BS2 -
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not specified Benign:5
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Primary erythromelalgia Uncertain:1Benign:1
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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
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Primary erythromelalgia;C1833661:Paroxysmal extreme pain disorder;C1855739:Channelopathy-associated congenital insensitivity to pain, autosomal recessive Uncertain:1
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
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
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Inherited Erythromelalgia Benign:1
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Inborn genetic diseases Benign:1
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
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
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Paroxysmal extreme pain disorder Benign:1
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:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at