rs773824421

Variant names:

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

Your query was ambiguous. Multiple possible variants found:

• chr2-166294664-T-C
• chr2-166294664-T-G

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The ENST00000447809.2(SCN1A-AS1):​n.1129T>C variant causes a non coding transcript exon change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SCN1A-AS1 ENST00000447809.2 non_coding_transcript_exon
• Clinical Significance: Not reported in ClinVar
• 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 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

Transcripts

RefSeq

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

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 26

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.20	D
BayesDel_noAF	Uncertain	0.040
CADD	Pathogenic	32
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
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=11/89	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.91		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.91		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;