2-166204478-C-A

Variant names:

• chr2-166204478-C-A
• rs112927502
• NM_001365536.1:c.4399-14G>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001365536.1(SCN9A):​c.4399-14G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000824 in 611,678 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00067 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00086 (5 hom.)
• Consequence: SCN9A NM_001365536.1 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -1.08
• Publications: 2 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 2-166204478-C-A is Benign according to our data. Variant chr2-166204478-C-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 258886.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.000671 (80/119206) while in subpopulation EAS AF = 0.0156 (61/3916). AF 95% confidence interval is 0.0124. There are 0 homozygotes in GnomAd4. There are 51 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 5 AD,SD,AR gene

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.4399-14G>T		intron	N/A	NP_001352465.1
	SCN9A	NM_002977.4		c.4366-14G>T		intron	N/A	NP_002968.2
	SCN1A-AS1	NR_110260.1		n.611+4660C>A		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SCN9A	ENST00000642356.2	MANE Select	c.4399-14G>T		intron	N/A	ENSP00000495601.1
	SCN9A	ENST00000303354.11	TSL:5	c.4399-14G>T		intron	N/A	ENSP00000304748.7
	SCN9A	ENST00000409672.5	TSL:5	c.4366-14G>T		intron	N/A	ENSP00000386306.1

Frequencies

GnomAD3 genomes AF: 0.000663 AC: 79 AN: 119100 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0158

Gnomad SAS AF: 0.00364

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000540

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00118 AC: 226 AN: 191076 AF XY: 0.00118

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0166

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000433

Gnomad OTH exome AF: 0.000235

GnomAD4 exome AF: 0.000861 AC: 424 AN: 492472 Hom.: 5 Cov.: 13 AF XY: 0.000879 AC XY: 226 AN XY: 257032

African (AFR) AF: 0.00 AC: 0 AN: 11358

American (AMR) AF: 0.000146 AC: 3 AN: 20604

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 11828

East Asian (EAS) AF: 0.0138 AC: 314 AN: 22706

South Asian (SAS) AF: 0.00165 AC: 68 AN: 41100

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 29334

Middle Eastern (MID) AF: 0.00110 AC: 2 AN: 1816

European-Non Finnish (NFE) AF: 0.0000121 AC: 4 AN: 329440

Other (OTH) AF: 0.00136 AC: 33 AN: 24286

GnomAD4 genome AF: 0.000671 AC: 80 AN: 119206 Hom.: 0 Cov.: 31 AF XY: 0.000883 AC XY: 51 AN XY: 57732

African (AFR) AF: 0.00 AC: 0 AN: 31342

American (AMR) AF: 0.00 AC: 0 AN: 11750

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2780

East Asian (EAS) AF: 0.0156 AC: 61 AN: 3916

South Asian (SAS) AF: 0.00416 AC: 16 AN: 3846

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 7420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 212

European-Non Finnish (NFE) AF: 0.0000540 AC: 3 AN: 55578

Other (OTH) AF: 0.00 AC: 0 AN: 1596

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	0.28
DANN	Benign	0.49
PhyloP100		-1.1
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs112927502; hg19: chr2-167060988; COSMIC: COSV57617017;