rs147352060

chr17-63972594-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000334.4(SCN4A):c.248T>C(p.Leu83Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000256 in 1,597,832 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0013 (3 hom., cov: 32)
  • Exomes 𝑓: 0.00014 (1 hom.)
• Consequence: SCN4A NM_000334.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 7.50

Genes affected

SCN4A (HGNC:10591): (sodium voltage-gated channel alpha subunit 4) Voltage-gated sodium channels are transmembrane glycoprotein complexes composed of a large alpha subunit with 24 transmembrane domains and one or more regulatory beta subunits. They are responsible for the generation and propagation of action potentials in neurons and muscle. This gene encodes one member of the sodium channel alpha subunit gene family. It is expressed in skeletal muscle, and mutations in this gene have been linked to several myotonia and periodic paralysis disorders. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.013655692).
• BP6: Variant 17-63972594-A-G is Benign according to our data. Variant chr17-63972594-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 426413.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-63972594-A-G is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00132 (201/152246) while in subpopulation AFR AF= 0.00474 (197/41550). AF 95% confidence interval is 0.0042. There are 3 homozygotes in gnomad4. There are 101 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 3 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SCN4A	NM_000334.4	c.248T>C	p.Leu83Pro	missense_variant	1/24	ENST00000435607.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SCN4A	ENST00000435607.3	c.248T>C	p.Leu83Pro	missense_variant	1/24	1	NM_000334.4	P1

Frequencies

GnomAD3 genomes AF: 0.00129 AC: 197 AN: 152128 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.00466

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000398 AC: 88 AN: 220952 Hom.: 1 AF XY: 0.000242 AC XY: 29 AN XY: 119636

Gnomad AFR exome AF: 0.00582

Gnomad AMR exome AF: 0.000229

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000359

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000102

Gnomad OTH exome AF: 0.000355

GnomAD4 exome AF: 0.000144 AC: 208 AN: 1445586 Hom.: 1 Cov.: 32 AF XY: 0.000120 AC XY: 86 AN XY: 717868

Gnomad4 AFR exome AF: 0.00487

Gnomad4 AMR exome AF: 0.000315

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000951

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000272

Gnomad4 OTH exome AF: 0.000351

GnomAD4 genome AF: 0.00132 AC: 201 AN: 152246 Hom.: 3 Cov.: 32 AF XY: 0.00136 AC XY: 101 AN XY: 74438

Gnomad4 AFR AF: 0.00474

Gnomad4 AMR AF: 0.000261

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000339 Hom.: 2

Bravo AF: 0.00163

ESP6500AA AF: 0.00339 AC: 14

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000480 AC: 58

Asia WGS AF: 0.00115 AC: 4 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 23, 2020	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2023	SCN4A: BS2 -

Hyperkalemic periodic paralysis Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 25, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.93
BayesDel_addAF	Benign	-0.0027	T
BayesDel_noAF	Pathogenic	0.23
Cadd	Uncertain	25
Dann	Uncertain	1.0
DEOGEN2	Pathogenic	0.81	D
Eigen	Benign	0.068
Eigen_PC	Benign	0.15
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.89	D
M_CAP	Pathogenic	0.32	D
MetaRNN	Benign	0.014	T
MetaSVM	Uncertain	0.65	D
MutationAssessor	Pathogenic	3.3	M
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.61	T
PROVEAN	Pathogenic	-5.4	D
REVEL	Pathogenic	0.77
Sift	Pathogenic	0.0	D
Sift4G	Benign	0.098	T
Polyphen		0.092	B
Vest4		0.39
MVP		0.90
MPC		0.63
ClinPred		0.19	T
GERP RS		4.3
Varity_R		0.81
gMVP		0.90

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

Publications

LitVar

Other links and lift over

dbSNP: rs147352060; hg19: chr17-62049954; COSMIC: COSV99076869; COSMIC: COSV99076869;