ENST00000447809.2:n.1129T>G

Variant names:

• chr2-166294664-T-G
• rs773824421
• ENST00000447809.2:n.1129T>G

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 3P and 1B. PP3_Moderate PP5 BS1_Supporting

The ENST00000447809.2(SCN1A-AS1):​n.1129T>G variant causes a non coding transcript exon change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000829 in 1,447,514 control chromosomes in the GnomAD database, with no homozygous occurrence. 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: not found (cov: 32)
  • Exomes 𝑓: 0.0000083 (0 hom.)
• Consequence: SCN1A-AS1 ENST00000447809.2 non_coding_transcript_exon
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:1
• Conservation: PhyloP100: 7.91
• Publications: 0 publications found

Genes affected

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

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 Gene-Disease associations (from GenCC):

• primary erythermalgia

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Orphanet, G2P
• generalized epilepsy with febrile seizures plus, type 7

  Inheritance: AD Classification: STRONG, LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• paroxysmal extreme pain disorder

  Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet
• channelopathy-associated congenital insensitivity to pain, autosomal recessive

  Inheritance: SD, AD, AR Classification: STRONG, SUPPORTIVE, LIMITED Submitted by: Ambry Genetics, Orphanet, Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae)
• sodium channelopathy-related small fiber neuropathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• hereditary sensory and autonomic neuropathy type 2

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• epilepsy

  Inheritance: AD Classification: LIMITED, NO_KNOWN Submitted by: Illumina, ClinGen

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant 2-166294664-T-G is Pathogenic according to our data. Variant chr2-166294664-T-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 408576.We mark this variant Likely_pathogenic, oryginal submission is: [Conflicting_classifications_of_pathogenicity].
• BS1: Variant frequency is greater than expected in population amr. GnomAdExome4 allele frequency = 0.00000829 (12/1447514) while in subpopulation AMR AF = 0.000274 (12/43778). AF 95% confidence interval is 0.000158. There are 0 homozygotes in GnomAdExome4. There are 4 alleles in the male GnomAdExome4 subpopulation. Median coverage is 26. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SCN9A	NM_001365536.1	c.902-2A>C		splice_acceptor_variant, intron_variant	Intron 7 of 26	ENST00000642356.2	NP_001352465.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SCN9A	ENST00000642356.2	c.902-2A>C		splice_acceptor_variant, intron_variant	Intron 7 of 26		NM_001365536.1	ENSP00000495601.1
SCN9A	ENST00000303354.11	c.902-2A>C		splice_acceptor_variant, intron_variant	Intron 7 of 26	5		ENSP00000304748.7
SCN9A	ENST00000409672.5	c.902-2A>C		splice_acceptor_variant, intron_variant	Intron 7 of 26	5		ENSP00000386306.1
SCN9A	ENST00000645907.1	c.902-2A>C		splice_acceptor_variant, intron_variant	Intron 7 of 26			ENSP00000495983.1
SCN9A	ENST00000454569.6	c.902-2A>C		splice_acceptor_variant, intron_variant	Intron 7 of 14	1		ENSP00000413212.2
SCN9A	ENST00000452182.2	c.902-2A>C		splice_acceptor_variant, intron_variant	Intron 8 of 10	1		ENSP00000393141.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000455 AC: 11 AN: 241528 AF XY: 0.0000229

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000337

Gnomad ASJ exome AF: 0.00

Gnomad EAS 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: 0.00000829 AC: 12 AN: 1447514 Hom.: 0 Cov.: 26 AF XY: 0.00000556 AC XY: 4 AN XY: 720032

African (AFR) AF: 0.00 AC: 0 AN: 33004

American (AMR) AF: 0.000274 AC: 12 AN: 43778

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25826

East Asian (EAS) AF: 0.00 AC: 0 AN: 39434

South Asian (SAS) AF: 0.00 AC: 0 AN: 83502

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53220

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5716

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1103240

Other (OTH) AF: 0.00 AC: 0 AN: 59794

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000113

ExAC AF: 0.0000248 AC: 3

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:1 Uncertain:1

May 14, 2020

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Canonical splice site variant in a gene for which loss-of-function is a known mechanism of disease; Has not been previously published as pathogenic or benign to our knowledge -

Oct 19, 2020

Revvity Omics, Revvity

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Generalized epilepsy with febrile seizures plus, type 7;C2752089:Neuropathy, hereditary sensory and autonomic, type 2A Pathogenic:1

Dec 09, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change affects an acceptor splice site in intron 7 of the SCN9A gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in SCN9A are known to be pathogenic (PMID: 17470132, 19304393). This variant is present in population databases (rs773824421, gnomAD 0.03%). Disruption of this splice site has been observed in individuals with clinical features of autosomal recessive hereditary sensory and autonomic neuropathy (internal data). ClinVar contains an entry for this variant (Variation ID: 408576). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.0065	T
BayesDel_noAF	Uncertain	0.060
CADD	Pathogenic	29
DANN	Uncertain	0.99
Eigen	Pathogenic	0.99
Eigen_PC	Pathogenic	0.80
FATHMM_MKL	Pathogenic	0.99	D
PhyloP100		7.9
GERP RS		4.6
Mutation Taster		=11/89	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.87		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.77		Position offset: 43
DS_AL_spliceai		0.87		Position offset: -2

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

Other links and lift over

dbSNP: rs773824421; hg19: chr2-167151174;