NM_006514.4:c.*123C>T

Variant names:

• chr3-38697226-G-A
• rs6599240
• NM_006514.4:c.*123C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_006514.4(SCN10A):​c.*123C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.443 in 1,470,942 control chromosomes in the GnomAD database, including 147,134 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.44 (14628 hom., cov: 32)
  • Exomes 𝑓: 0.44 (132506 hom.)
• Consequence: SCN10A NM_006514.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.649
• Publications: 8 publications found

Genes affected

SCN10A (HGNC:10582): (sodium voltage-gated channel alpha subunit 10) The protein encoded by this gene is a tetrodotoxin-resistant voltage-gated sodium channel alpha subunit. The properties of the channel formed by the encoded transmembrane protein can be altered by interaction with different beta subunits. This protein may be involved in the onset of pain associated with peripheral neuropathy. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jun 2014]

SCN10A Gene-Disease associations (from GenCC):

• sodium channelopathy-related small fiber neuropathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• episodic pain syndrome, familial, 2

  Inheritance: AD Classification: LIMITED, NO_KNOWN Submitted by: Labcorp Genetics (formerly Invitae), Illumina, Ambry Genetics
• Brugada syndrome

  Inheritance: Unknown Classification: LIMITED Submitted by: Genomics England PanelApp
• Brugada syndrome 1

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.73).
• BP6: Variant 3-38697226-G-A is Benign according to our data. Variant chr3-38697226-G-A is described in ClinVar as [Benign]. Clinvar id is 1259657.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.45 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SCN10A	NM_006514.4	c.*123C>T		3_prime_UTR_variant	Exon 28 of 28	ENST00000449082.3	NP_006505.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SCN10A	ENST00000449082.3	c.*123C>T		3_prime_UTR_variant	Exon 28 of 28	1	NM_006514.4	ENSP00000390600.2
SCN10A	ENST00000655275.1	c.*123C>T		3_prime_UTR_variant	Exon 28 of 28			ENSP00000499510.1
SCN10A	ENST00000643924.1	c.*123C>T		downstream_gene_variant				ENSP00000495595.1

Frequencies

GnomAD3 genomes AF: 0.437 AC: 66303 AN: 151894 Hom.: 14636 Cov.: 32

Gnomad AFR AF: 0.449

Gnomad AMI AF: 0.482

Gnomad AMR AF: 0.402

Gnomad ASJ AF: 0.419

Gnomad EAS AF: 0.138

Gnomad SAS AF: 0.412

Gnomad FIN AF: 0.477

Gnomad MID AF: 0.519

Gnomad NFE AF: 0.454

Gnomad OTH AF: 0.455

GnomAD4 exome AF: 0.444 AC: 585843 AN: 1318930 Hom.: 132506 Cov.: 21 AF XY: 0.445 AC XY: 287556 AN XY: 646802

African (AFR) AF: 0.458 AC: 13585 AN: 29690

American (AMR) AF: 0.375 AC: 11160 AN: 29742

Ashkenazi Jewish (ASJ) AF: 0.417 AC: 8312 AN: 19942

East Asian (EAS) AF: 0.128 AC: 4919 AN: 38500

South Asian (SAS) AF: 0.434 AC: 29527 AN: 68062

European-Finnish (FIN) AF: 0.465 AC: 18491 AN: 39746

Middle Eastern (MID) AF: 0.480 AC: 1766 AN: 3676

European-Non Finnish (NFE) AF: 0.458 AC: 474325 AN: 1034762

Other (OTH) AF: 0.433 AC: 23758 AN: 54810

GnomAD4 genome AF: 0.436 AC: 66308 AN: 152012 Hom.: 14628 Cov.: 32 AF XY: 0.432 AC XY: 32106 AN XY: 74296

African (AFR) AF: 0.448 AC: 18576 AN: 41442

American (AMR) AF: 0.402 AC: 6146 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.419 AC: 1451 AN: 3466

East Asian (EAS) AF: 0.138 AC: 713 AN: 5174

South Asian (SAS) AF: 0.411 AC: 1976 AN: 4808

European-Finnish (FIN) AF: 0.477 AC: 5038 AN: 10560

Middle Eastern (MID) AF: 0.514 AC: 151 AN: 294

European-Non Finnish (NFE) AF: 0.454 AC: 30864 AN: 67962

Other (OTH) AF: 0.452 AC: 953 AN: 2110

Alfa AF: 0.445 Hom.: 50167

Bravo AF: 0.430

Asia WGS AF: 0.297 AC: 1036 AN: 3476

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jun 19, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.73
CADD	Benign	10
DANN	Benign	0.77
PhyloP100		0.65
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs6599240; hg19: chr3-38738717; COSMIC: COSV71862339; COSMIC: COSV71862339;