2-166195818-A-G

Variant names:

• chr2-166195818-A-G
• rs73017538
• NM_001365536.1:c.*2854T>C

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.*2854T>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.109 in 152,234 control chromosomes in the GnomAD database, including 1,029 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.11 (1028 hom., cov: 32)
  • Exomes 𝑓: 0.15 (1 hom.)
• Consequence: SCN9A NM_001365536.1 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.823

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 2-166195818-A-G is Benign according to our data. Variant chr2-166195818-A-G is described in ClinVar as [Benign]. Clinvar id is 331903.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.165 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SCN9A	NM_001365536.1	c.*2854T>C		3_prime_UTR_variant	Exon 27 of 27	ENST00000642356.2	NP_001352465.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SCN9A	ENST00000642356	c.*2854T>C		3_prime_UTR_variant	Exon 27 of 27		NM_001365536.1	ENSP00000495601.1
SCN9A	ENST00000303354	c.*2854T>C		3_prime_UTR_variant	Exon 27 of 27	5		ENSP00000304748.7
SCN9A	ENST00000409672	c.*2854T>C		3_prime_UTR_variant	Exon 27 of 27	5		ENSP00000386306.1

Frequencies

GnomAD3 genomes AF: 0.109 AC: 16519 AN: 152082 Hom.: 1026 Cov.: 32

Gnomad AFR AF: 0.168

Gnomad AMI AF: 0.0932

Gnomad AMR AF: 0.0806

Gnomad ASJ AF: 0.120

Gnomad EAS AF: 0.0233

Gnomad SAS AF: 0.0723

Gnomad FIN AF: 0.0775

Gnomad MID AF: 0.0886

Gnomad NFE AF: 0.0923

Gnomad OTH AF: 0.117

GnomAD4 exome AF: 0.147 AC: 5 AN: 34 Hom.: 1 Cov.: 0 AF XY: 0.179 AC XY: 5 AN XY: 28

Gnomad4 EAS exome AF: 0.00

Gnomad4 NFE exome AF: 0.154

Gnomad4 OTH exome AF: 0.167

GnomAD4 genome AF: 0.109 AC: 16542 AN: 152200 Hom.: 1028 Cov.: 32 AF XY: 0.106 AC XY: 7907 AN XY: 74422

Gnomad4 AFR AF: 0.168

Gnomad4 AMR AF: 0.0805

Gnomad4 ASJ AF: 0.120

Gnomad4 EAS AF: 0.0231

Gnomad4 SAS AF: 0.0732

Gnomad4 FIN AF: 0.0775

Gnomad4 NFE AF: 0.0923

Gnomad4 OTH AF: 0.116

Alfa AF: 0.110 Hom.: 130

Bravo AF: 0.110

Asia WGS AF: 0.0630 AC: 220 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Primary erythromelalgia Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Inherited Erythromelalgia Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Paroxysmal extreme pain disorder Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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	1.0
DANN	Benign	0.53

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: rs73017538; hg19: chr2-167052328;