NM_001365536.1:c.4399-10_4399-7delGTTT

Variant names:

• chr2-166204470-GAAAC-G
• rs77944059
• NM_001365536.1:c.4399-10_4399-7delGTTT

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.4399-10_4399-7delGTTT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.871 in 1,507,680 control chromosomes in the GnomAD database, including 573,967 homozygotes. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.89 (60110 hom., cov: 0)
  • Exomes 𝑓: 0.87 (513857 hom.)
• Consequence: SCN9A NM_001365536.1 splice_region, intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:15
• Conservation: PhyloP100: 0.886
• Publications: 5 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 2-166204470-GAAAC-G is Benign according to our data. Variant chr2-166204470-GAAAC-G is described in ClinVar as Benign. ClinVar VariationId is 167657.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.929 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.4399-10_4399-7delGTTT		splice_region intron	N/A	NP_001352465.1	Q15858-1
	SCN9A	NM_002977.4		c.4366-10_4366-7delGTTT		splice_region intron	N/A	NP_002968.2	Q15858-3
	SCN1A-AS1	NR_110260.1		n.611+4660_611+4663delCAAA		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SCN9A	ENST00000642356.2	MANE Select	c.4399-10_4399-7delGTTT		splice_region intron	N/A	ENSP00000495601.1	Q15858-1
	SCN9A	ENST00000303354.11	TSL:5	c.4399-10_4399-7delGTTT		splice_region intron	N/A	ENSP00000304748.7	Q15858-1
	SCN9A	ENST00000409672.5	TSL:5	c.4366-10_4366-7delGTTT		splice_region intron	N/A	ENSP00000386306.1	Q15858-3

Frequencies

GnomAD3 genomes AF: 0.890 AC: 134739 AN: 151410 Hom.: 60067 Cov.: 0

Gnomad AFR AF: 0.937

Gnomad AMI AF: 0.867

Gnomad AMR AF: 0.886

Gnomad ASJ AF: 0.910

Gnomad EAS AF: 0.937

Gnomad SAS AF: 0.828

Gnomad FIN AF: 0.886

Gnomad MID AF: 0.879

Gnomad NFE AF: 0.863

Gnomad OTH AF: 0.883

GnomAD2 exomes AF: 0.881 AC: 195432 AN: 221844 AF XY: 0.877

Gnomad AFR exome AF: 0.938

Gnomad AMR exome AF: 0.903

Gnomad ASJ exome AF: 0.911

Gnomad EAS exome AF: 0.938

Gnomad FIN exome AF: 0.892

Gnomad NFE exome AF: 0.864

Gnomad OTH exome AF: 0.875

GnomAD4 exome AF: 0.869 AC: 1178638 AN: 1356152 Hom.: 513857 AF XY: 0.868 AC XY: 586267 AN XY: 675432

African (AFR) AF: 0.937 AC: 28230 AN: 30118

American (AMR) AF: 0.899 AC: 31883 AN: 35464

Ashkenazi Jewish (ASJ) AF: 0.907 AC: 21670 AN: 23894

East Asian (EAS) AF: 0.940 AC: 36477 AN: 38810

South Asian (SAS) AF: 0.836 AC: 61822 AN: 73968

European-Finnish (FIN) AF: 0.894 AC: 46577 AN: 52102

Middle Eastern (MID) AF: 0.867 AC: 3325 AN: 3834

European-Non Finnish (NFE) AF: 0.863 AC: 899374 AN: 1041828

Other (OTH) AF: 0.878 AC: 49280 AN: 56134

GnomAD4 genome AF: 0.890 AC: 134838 AN: 151528 Hom.: 60110 Cov.: 0 AF XY: 0.889 AC XY: 65760 AN XY: 74008

African (AFR) AF: 0.937 AC: 38809 AN: 41410

American (AMR) AF: 0.886 AC: 13463 AN: 15200

Ashkenazi Jewish (ASJ) AF: 0.910 AC: 3154 AN: 3466

East Asian (EAS) AF: 0.937 AC: 4839 AN: 5162

South Asian (SAS) AF: 0.826 AC: 3970 AN: 4804

European-Finnish (FIN) AF: 0.886 AC: 9271 AN: 10464

Middle Eastern (MID) AF: 0.884 AC: 258 AN: 292

European-Non Finnish (NFE) AF: 0.863 AC: 58428 AN: 67716

Other (OTH) AF: 0.883 AC: 1857 AN: 2104

Alfa AF: 0.884 Hom.: 10776

Bravo AF: 0.895

Asia WGS AF: 0.878 AC: 3027 AN: 3448

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	-	2	not provided (2)
-	-	2	Paroxysmal extreme pain disorder (2)
-	-	1	Channelopathy-associated congenital insensitivity to pain, autosomal recessive (1)
-	-	1	Congenital Indifference to Pain (1)
-	-	1	Generalized epilepsy with febrile seizures plus, type 7;C2752089:Neuropathy, hereditary sensory and autonomic, type 2A (1)
-	-	1	Inherited Erythromelalgia (1)
-	-	1	Primary erythromelalgia (1)
-	-	1	Small fiber neuropathy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.89
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs77944059; hg19: chr2-167060980;