rs4447616

Variant names:

• chr2-166307153-C-T
• rs4447616
• NM_001365536.1:c.259-79G>A

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_001365536.1(SCN9A):​c.259-79G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.633 in 786,280 control chromosomes in the GnomAD database, including 160,867 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.67 (35589 hom., cov: 31)
  • Exomes 𝑓: 0.62 (125278 hom.)
• Consequence: SCN9A NM_001365536.1 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.22
• Publications: 11 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BP6: Variant 2-166307153-C-T is Benign according to our data. Variant chr2-166307153-C-T is described in ClinVar as Benign. ClinVar VariationId is 3255239.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.826 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SCN9A	NM_001365536.1	c.259-79G>A		intron_variant	Intron 2 of 26	ENST00000642356.2	NP_001352465.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SCN9A	ENST00000642356.2	c.259-79G>A		intron_variant	Intron 2 of 26		NM_001365536.1	ENSP00000495601.1
SCN9A	ENST00000303354.11	c.259-79G>A		intron_variant	Intron 2 of 26	5		ENSP00000304748.7
SCN9A	ENST00000409672.5	c.259-79G>A		intron_variant	Intron 2 of 26	5		ENSP00000386306.1
SCN9A	ENST00000645907.1	c.259-79G>A		intron_variant	Intron 2 of 26			ENSP00000495983.1
SCN9A	ENST00000454569.6	c.259-79G>A		intron_variant	Intron 2 of 14	1		ENSP00000413212.2
SCN9A	ENST00000452182.2	c.259-79G>A		intron_variant	Intron 3 of 10	1		ENSP00000393141.2

Frequencies

GnomAD3 genomes AF: 0.674 AC: 102389 AN: 151864 Hom.: 35550 Cov.: 31

Gnomad AFR AF: 0.834

Gnomad AMI AF: 0.740

Gnomad AMR AF: 0.569

Gnomad ASJ AF: 0.521

Gnomad EAS AF: 0.429

Gnomad SAS AF: 0.546

Gnomad FIN AF: 0.600

Gnomad MID AF: 0.551

Gnomad NFE AF: 0.648

Gnomad OTH AF: 0.668

GnomAD4 exome AF: 0.623 AC: 395351 AN: 634300 Hom.: 125278 AF XY: 0.620 AC XY: 208391 AN XY: 336060

African (AFR) AF: 0.832 AC: 13782 AN: 16574

American (AMR) AF: 0.480 AC: 14971 AN: 31172

Ashkenazi Jewish (ASJ) AF: 0.529 AC: 9657 AN: 18268

East Asian (EAS) AF: 0.463 AC: 14913 AN: 32228

South Asian (SAS) AF: 0.552 AC: 31379 AN: 56850

European-Finnish (FIN) AF: 0.602 AC: 28396 AN: 47152

Middle Eastern (MID) AF: 0.562 AC: 1715 AN: 3052

European-Non Finnish (NFE) AF: 0.656 AC: 260334 AN: 396942

Other (OTH) AF: 0.630 AC: 20204 AN: 32062

GnomAD4 genome AF: 0.674 AC: 102473 AN: 151980 Hom.: 35589 Cov.: 31 AF XY: 0.666 AC XY: 49465 AN XY: 74266

African (AFR) AF: 0.834 AC: 34601 AN: 41506

American (AMR) AF: 0.568 AC: 8669 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.521 AC: 1804 AN: 3464

East Asian (EAS) AF: 0.430 AC: 2211 AN: 5146

South Asian (SAS) AF: 0.546 AC: 2634 AN: 4822

European-Finnish (FIN) AF: 0.600 AC: 6329 AN: 10542

Middle Eastern (MID) AF: 0.558 AC: 164 AN: 294

European-Non Finnish (NFE) AF: 0.648 AC: 43989 AN: 67916

Other (OTH) AF: 0.663 AC: 1399 AN: 2110

Alfa AF: 0.655 Hom.: 13044

Bravo AF: 0.675

Asia WGS AF: 0.511 AC: 1779 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Jul 15, 2024

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is classified as Benign based on local population frequency. This variant was detected in 76% of patients studied in a panel designed for Epileptic and Developmental Encephalopathy and Progressive Myoclonus Epilepsy. Number of patients: 71. Only high quality variants are reported. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	9.6
DANN	Benign	0.74
PhyloP100		-1.2
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.20		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.20		Position offset: -4

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

Other links and lift over

dbSNP: rs4447616; hg19: chr2-167163663; COSMIC: COSV57629742; COSMIC: COSV57629742;