chr2-166199827-C-A

Variant names:

• chr2-166199827-C-A
• rs149207258
• NM_001365536.1:c.4812G>T

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_001365536.1(SCN9A):​c.4812G>T​(p.Val1604Val) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0766 in 1,613,646 control chromosomes in the GnomAD database, including 5,262 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.065 (369 hom., cov: 31)
  • Exomes 𝑓: 0.078 (4893 hom.)
• Consequence: SCN9A NM_001365536.1 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:13
• Conservation: PhyloP100: 0.0770
• Publications: 8 publications found

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

Our verdict: Benign. The variant received -16 ACMG points.

• BP6: Variant 2-166199827-C-A is Benign according to our data. Variant chr2-166199827-C-A is described in ClinVar as Benign. ClinVar VariationId is 130270.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0859 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001365536.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SCN9A	NM_001365536.1	MANE Select	c.4812G>T	p.Val1604Val	synonymous	Exon 27 of 27	NP_001352465.1	Q15858-1
	SCN9A	NM_002977.4		c.4779G>T	p.Val1593Val	synonymous	Exon 27 of 27	NP_002968.2	Q15858-3
	SCN1A-AS1	NR_110260.1		n.611+9C>A		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SCN9A	ENST00000642356.2	MANE Select	c.4812G>T	p.Val1604Val	synonymous	Exon 27 of 27	ENSP00000495601.1	Q15858-1
	SCN9A	ENST00000303354.11	TSL:5	c.4812G>T	p.Val1604Val	synonymous	Exon 27 of 27	ENSP00000304748.7	Q15858-1
	SCN9A	ENST00000409672.5	TSL:5	c.4779G>T	p.Val1593Val	synonymous	Exon 27 of 27	ENSP00000386306.1	Q15858-3

Frequencies

GnomAD3 genomes AF: 0.0646 AC: 9802 AN: 151768 Hom.: 369 Cov.: 31

Gnomad AFR AF: 0.0364

Gnomad AMI AF: 0.0932

Gnomad AMR AF: 0.0566

Gnomad ASJ AF: 0.0706

Gnomad EAS AF: 0.0143

Gnomad SAS AF: 0.0189

Gnomad FIN AF: 0.0776

Gnomad MID AF: 0.0633

Gnomad NFE AF: 0.0878

Gnomad OTH AF: 0.0670

GnomAD2 exomes AF: 0.0616 AC: 15485 AN: 251428 AF XY: 0.0616

Gnomad AFR exome AF: 0.0347

Gnomad AMR exome AF: 0.0356

Gnomad ASJ exome AF: 0.0730

Gnomad EAS exome AF: 0.0153

Gnomad FIN exome AF: 0.0805

Gnomad NFE exome AF: 0.0854

Gnomad OTH exome AF: 0.0670

GnomAD4 exome AF: 0.0779 AC: 113849 AN: 1461760 Hom.: 4893 Cov.: 33 AF XY: 0.0764 AC XY: 55537 AN XY: 727194

African (AFR) AF: 0.0333 AC: 1114 AN: 33476

American (AMR) AF: 0.0373 AC: 1669 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.0727 AC: 1899 AN: 26136

East Asian (EAS) AF: 0.00887 AC: 352 AN: 39698

South Asian (SAS) AF: 0.0258 AC: 2223 AN: 86254

European-Finnish (FIN) AF: 0.0804 AC: 4297 AN: 53416

Middle Eastern (MID) AF: 0.0477 AC: 275 AN: 5766

European-Non Finnish (NFE) AF: 0.0877 AC: 97536 AN: 1111912

Other (OTH) AF: 0.0743 AC: 4484 AN: 60382

GnomAD4 genome AF: 0.0645 AC: 9803 AN: 151886 Hom.: 369 Cov.: 31 AF XY: 0.0622 AC XY: 4613 AN XY: 74220

African (AFR) AF: 0.0364 AC: 1506 AN: 41412

American (AMR) AF: 0.0565 AC: 862 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.0706 AC: 245 AN: 3470

East Asian (EAS) AF: 0.0142 AC: 73 AN: 5158

South Asian (SAS) AF: 0.0196 AC: 94 AN: 4800

European-Finnish (FIN) AF: 0.0776 AC: 817 AN: 10530

Middle Eastern (MID) AF: 0.0680 AC: 20 AN: 294

European-Non Finnish (NFE) AF: 0.0877 AC: 5961 AN: 67932

Other (OTH) AF: 0.0664 AC: 140 AN: 2110

Alfa AF: 0.0787 Hom.: 230

Bravo AF: 0.0616

Asia WGS AF: 0.0160 AC: 55 AN: 3478

EpiCase AF: 0.0862

EpiControl AF: 0.0792

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	2	Channelopathy-associated congenital insensitivity to pain, autosomal recessive (2)
-	-	2	not specified (2)
-	-	2	Paroxysmal extreme pain disorder (2)
-	-	2	Primary erythromelalgia (2)
-	-	1	Generalized epilepsy with febrile seizures plus, type 7;C2752089:Neuropathy, hereditary sensory and autonomic, type 2A (1)
-	-	1	Inherited Erythromelalgia (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.33
CADD	Benign	14
DANN	Benign	0.82
PhyloP100		0.077
Mutation Taster		=80/20	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.27		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.27		Position offset: -20

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

Other links and lift over

dbSNP: rs149207258; hg19: chr2-167056337; COSMIC: COSV57627632;