11-118144025-G-T

Variant names:

• chr11-118144025-G-T
• rs113659925
• NM_174934.4:c.271C>A

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BS2

The NM_174934.4(SCN4B):​c.271C>A​(p.Pro91Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00000889 in 1,461,748 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P91S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000089 (0 hom.)
• Consequence: SCN4B NM_174934.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.21
• Publications: 0 publications found

Genes affected

SCN4B (HGNC:10592): (sodium voltage-gated channel beta subunit 4) The protein encoded by this gene is one of several sodium channel beta subunits. These subunits interact with voltage-gated alpha subunits to change sodium channel kinetics. The encoded transmembrane protein forms interchain disulfide bonds with SCN2A. Defects in this gene are a cause of long QT syndrome type 10 (LQT10). Three protein-coding and one non-coding transcript variant have been found for this gene.[provided by RefSeq, Mar 2009]

SCN4B Gene-Disease associations (from GenCC):

• familial atrial fibrillation

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• long QT syndrome 10

  Inheritance: AD, Unknown Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine
• long QT syndrome

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• BS2: High AC in GnomAdExome4 at 13 AD,Unknown gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_174934.4. 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
	SCN4B	NM_174934.4	MANE Select	c.271C>A	p.Pro91Thr	missense	Exon 3 of 5	NP_777594.1	Q8IWT1-1
	SCN4B	NM_001142349.2		c.-60C>A		5_prime_UTR	Exon 2 of 4	NP_001135821.1	Q8IWT1-2
	SCN4B	NM_001142348.2		c.62-2689C>A		intron	N/A	NP_001135820.1	Q8IWT1-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SCN4B	ENST00000324727.9	TSL:1 MANE Select	c.271C>A	p.Pro91Thr	missense	Exon 3 of 5	ENSP00000322460.4	Q8IWT1-1
	SCN4B	ENST00000415030.6	TSL:1	n.414C>A		non_coding_transcript_exon	Exon 2 of 4
	SCN4B	ENST00000529878.1	TSL:4	c.62-2689C>A		intron	N/A	ENSP00000436343.1	Q8IWT1-3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000889 AC: 13 AN: 1461748 Hom.: 0 Cov.: 32 AF XY: 0.00000688 AC XY: 5 AN XY: 727188

African (AFR) AF: 0.00 AC: 0 AN: 33476

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53410

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.0000117 AC: 13 AN: 1111892

Other (OTH) AF: 0.00 AC: 0 AN: 60390

GnomAD4 genome Cov.: 32

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Primary dilated cardiomyopathy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.75
BayesDel_addAF	Benign	-0.021	T
BayesDel_noAF	Benign	-0.27
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.56	D
Eigen	Uncertain	0.55
Eigen_PC	Uncertain	0.49
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Benign	0.79	T
M_CAP	Uncertain	0.11	D
MetaRNN	Uncertain	0.74	D
MetaSVM	Benign	-0.32	T
MutationAssessor	Pathogenic	3.0	M
PhyloP100		5.2
PrimateAI	Benign	0.45	T
PROVEAN	Pathogenic	-5.0	D
REVEL	Uncertain	0.38
Sift	Uncertain	0.0070	D
Sift4G	Uncertain	0.0070	D
Polyphen		1.0	D
Vest4		0.61
MutPred		0.45		Loss of stability (P = 0.0413)
MVP		0.29
MPC		0.66
ClinPred		1.0	D
GERP RS		3.9
Varity_R		0.71
gMVP		0.79
Mutation Taster		=62/38	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs113659925; hg19: chr11-118014740;