2-166281810-TA-T

Position:

• chr2-166281810-TA-T

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_Strong BS1 BS2

The NM_001365536.1(SCN9A):​c.1975-3del variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00496 in 1,374,896 control chromosomes in the GnomAD database, including 24 homozygotes. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00080 (3 hom., cov: 31)
  • Exomes 𝑓: 0.0055 (21 hom.)
• Consequence: SCN9A NM_001365536.1 splice_region, splice_polypyrimidine_tract, intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: -0.261

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)

ACMG classification

Verdict is Benign. Variant got -16 ACMG points.

• BP6: Variant 2-166281810-TA-T is Benign according to our data. Variant chr2-166281810-TA-T is described in ClinVar as [Likely_benign]. Clinvar id is 194207.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-166281810-TA-T is described in Lovd as [Benign]. Variant chr2-166281810-TA-T is described in Lovd as [Likely_benign]. Variant chr2-166281810-TA-T is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.000797 (119/149306) while in subpopulation SAS AF= 0.0204 (96/4700). AF 95% confidence interval is 0.0171. There are 3 homozygotes in gnomad4. There are 76 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 3 SD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SCN9A	NM_001365536.1	c.1975-3del		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000642356.2	NP_001352465.1
SCN1A-AS1	NR_110260.1	n.1029+4573del		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SCN9A	ENST00000642356.2	c.1975-3del		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant			NM_001365536.1	ENSP00000495601	P1
SCN1A-AS1	ENST00000651574.1	n.1707+4573del		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.000771 AC: 115 AN: 149216 Hom.: 3 Cov.: 31

Gnomad AFR AF: 0.000246

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000389

Gnomad SAS AF: 0.0199

Gnomad FIN AF: 0.000201

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000104

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00547 AC: 6702 AN: 1225590 Hom.: 21 Cov.: 29 AF XY: 0.00607 AC XY: 3689 AN XY: 607628

Gnomad4 AFR exome AF: 0.00527

Gnomad4 AMR exome AF: 0.0112

Gnomad4 ASJ exome AF: 0.00689

Gnomad4 EAS exome AF: 0.00490

Gnomad4 SAS exome AF: 0.0287

Gnomad4 FIN exome AF: 0.00582

Gnomad4 NFE exome AF: 0.00358

Gnomad4 OTH exome AF: 0.00604

GnomAD4 genome AF: 0.000797 AC: 119 AN: 149306 Hom.: 3 Cov.: 31 AF XY: 0.00104 AC XY: 76 AN XY: 72850

Gnomad4 AFR AF: 0.000294

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000390

Gnomad4 SAS AF: 0.0204

Gnomad4 FIN AF: 0.000201

Gnomad4 NFE AF: 0.000104

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0208 Hom.: 30

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jan 07, 2015	- -

Inherited Erythromelalgia Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Generalized epilepsy with febrile seizures plus Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

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

Jan 31, 2024

- -

Congenital Indifference to Pain Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Small fiber neuropathy Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Paroxysmal extreme pain disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Febrile seizures, familial Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Severe myoclonic epilepsy in infancy Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Computational scores

Source: dbNSFP v4.3

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

Other links and lift over

dbSNP: rs35888674; hg19: chr2-167138320;