chr3-38723544-C-A

Variant names:

• chr3-38723544-C-A
• rs376528831
• NM_006514.4:c.3238G>T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_006514.4(SCN10A):​c.3238G>T​(p.Asp1080Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000693 in 1,442,368 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D1080N) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: SCN10A NM_006514.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.22
• Publications: 0 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: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.36648116).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SCN10A	NM_006514.4	c.3238G>T	p.Asp1080Tyr	missense_variant	Exon 19 of 28	ENST00000449082.3	NP_006505.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SCN10A	ENST00000449082.3	c.3238G>T	p.Asp1080Tyr	missense_variant	Exon 19 of 28	1	NM_006514.4	ENSP00000390600.2
SCN10A	ENST00000643924.1	c.3235G>T	p.Asp1079Tyr	missense_variant	Exon 18 of 27			ENSP00000495595.1
SCN10A	ENST00000655275.1	c.3262G>T	p.Asp1088Tyr	missense_variant	Exon 19 of 28			ENSP00000499510.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.93e-7 AC: 1 AN: 1442368 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 716004

African (AFR) AF: 0.00 AC: 0 AN: 33046

American (AMR) AF: 0.00 AC: 0 AN: 41038

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25776

East Asian (EAS) AF: 0.00 AC: 0 AN: 38708

South Asian (SAS) AF: 0.00 AC: 0 AN: 84154

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52382

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5752

European-Non Finnish (NFE) AF: 9.08e-7 AC: 1 AN: 1101832

Other (OTH) AF: 0.00 AC: 0 AN: 59680

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Uncertain	0.078	D
BayesDel_noAF	Benign	-0.13
CADD	Benign	17
DANN	Uncertain	0.99
DEOGEN2	Benign	0.19	T;.;T;.
Eigen	Uncertain	0.27
Eigen_PC	Benign	0.16
FATHMM_MKL	Benign	0.23	N
LIST_S2	Uncertain	0.88	.;D;D;D
M_CAP	Benign	0.061	D
MetaRNN	Benign	0.37	T;T;T;T
MetaSVM	Uncertain	-0.0099	T
MutationAssessor	Uncertain	2.4	M;.;M;.
PhyloP100		1.2
PrimateAI	Benign	0.39	T
PROVEAN	Uncertain	-3.0	D;.;.;.
REVEL	Uncertain	0.38
Sift	Uncertain	0.0090	D;.;.;.
Sift4G	Uncertain	0.014	D;.;.;.
Polyphen		1.0	D;.;D;.
Vest4		0.55
MutPred		0.43		Gain of glycosylation at S1082 (P = 0.0122);Gain of glycosylation at S1082 (P = 0.0122);Gain of glycosylation at S1082 (P = 0.0122);.;
MVP		0.81
MPC		0.083
ClinPred		0.96	D
GERP RS		4.8
Varity_R		0.13
gMVP		0.50
Mutation Taster		=92/8	polymorphism

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: rs376528831; hg19: chr3-38765035;