chr2-166196032-C-T

Position:

• chr2-166196032-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001365536.1(SCN9A):​c.*2640G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.433 in 151,920 control chromosomes in the GnomAD database, including 14,538 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.43 (14538 hom., cov: 32)
  • Exomes 𝑓: 0.65 (5 hom.)
  • Failed GnomAD Quality Control
• Consequence: SCN9A NM_001365536.1 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:4
• Conservation: PhyloP100: -4.34

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-1.04).
• BP6: Variant 2-166196032-C-T is Benign according to our data. Variant chr2-166196032-C-T is described in ClinVar as [Benign]. Clinvar id is 331907.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.472 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SCN9A	NM_001365536.1	c.*2640G>A		3_prime_UTR_variant	27/27	ENST00000642356.2
SCN1A-AS1	NR_110260.1	n.432-3607C>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SCN9A	ENST00000642356.2	c.*2640G>A		3_prime_UTR_variant	27/27		NM_001365536.1	P1
SCN1A-AS1	ENST00000651574.1	n.1110-3607C>T		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.433 AC: 65799 AN: 151802 Hom.: 14541 Cov.: 32

Gnomad AFR AF: 0.387

Gnomad AMI AF: 0.422

Gnomad AMR AF: 0.334

Gnomad ASJ AF: 0.472

Gnomad EAS AF: 0.432

Gnomad SAS AF: 0.472

Gnomad FIN AF: 0.458

Gnomad MID AF: 0.449

Gnomad NFE AF: 0.476

Gnomad OTH AF: 0.433

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.654 AC: 17 AN: 26 Hom.: 5 Cov.: 0 AF XY: 0.611 AC XY: 11 AN XY: 18

Gnomad4 AFR exome AF: 1.00

Gnomad4 EAS exome AF: 0.500

Gnomad4 NFE exome AF: 0.650

GnomAD4 genome AF: 0.433 AC: 65806 AN: 151920 Hom.: 14538 Cov.: 32 AF XY: 0.430 AC XY: 31906 AN XY: 74242

Gnomad4 AFR AF: 0.386

Gnomad4 AMR AF: 0.334

Gnomad4 ASJ AF: 0.472

Gnomad4 EAS AF: 0.432

Gnomad4 SAS AF: 0.469

Gnomad4 FIN AF: 0.458

Gnomad4 NFE AF: 0.476

Gnomad4 OTH AF: 0.432

Alfa AF: 0.461 Hom.: 2030

Bravo AF: 0.423

Asia WGS AF: 0.447 AC: 1556 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, single submitter

Submissions by phenotype

Primary erythromelalgia Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

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. -

Channelopathy-associated congenital insensitivity to pain, autosomal recessive Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

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. -

Small fiber neuropathy Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Paroxysmal extreme pain disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

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: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	0.15
DANN	Benign	0.48

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: rs13396526; hg19: chr2-167052542;