20-33412656-C-T

Variant names:

• chr20-33412656-C-T
• rs35938843
• NM_003098.3:c.828G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Moderate BP6 BP7 BS1 BS2

The NM_003098.3(SNTA1):​c.828G>A​(p.Lys276Lys) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0148 in 1,613,964 control chromosomes in the GnomAD database, including 227 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.010 (15 hom., cov: 32)
  • Exomes 𝑓: 0.015 (212 hom.)
• Consequence: SNTA1 NM_003098.3 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:5
• Conservation: PhyloP100: 0.266
• Publications: 5 publications found

Genes affected

SNTA1 (HGNC:11167): (syntrophin alpha 1) Syntrophins are cytoplasmic peripheral membrane scaffold proteins that are components of the dystrophin-associated protein complex. This gene is a member of the syntrophin gene family and encodes the most common syntrophin isoform found in cardiac tissues. The N-terminal PDZ domain of this syntrophin protein interacts with the C-terminus of the pore-forming alpha subunit (SCN5A) of the cardiac sodium channel Nav1.5. This protein also associates cardiac sodium channels with the nitric oxide synthase-PMCA4b (plasma membrane Ca-ATPase subtype 4b) complex in cardiomyocytes. This gene is a susceptibility locus for Long-QT syndrome (LQT) - an inherited disorder associated with sudden cardiac death from arrhythmia - and sudden infant death syndrome (SIDS). This protein also associates with dystrophin and dystrophin-related proteins at the neuromuscular junction and alters intracellular calcium ion levels in muscle tissue. [provided by RefSeq, Jan 2013]

SNTA1 Gene-Disease associations (from GenCC):

• long QT syndrome 12

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• long QT syndrome

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

LOC124904889 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.43).
• BP6: Variant 20-33412656-C-T is Benign according to our data. Variant chr20-33412656-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 220958.
• BP7: Synonymous conserved (PhyloP=0.266 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0101 (1531/152312) while in subpopulation NFE AF = 0.017 (1153/68022). AF 95% confidence interval is 0.0161. There are 15 homozygotes in GnomAd4. There are 698 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 1531 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003098.3. 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
	SNTA1	NM_003098.3	MANE Select	c.828G>A	p.Lys276Lys	synonymous	Exon 4 of 8	NP_003089.1	Q13424-1
	SNTA1	NM_001424413.1		c.828G>A	p.Lys276Lys	synonymous	Exon 4 of 8	NP_001411342.1
	SNTA1	NM_001424414.1		c.828G>A	p.Lys276Lys	synonymous	Exon 4 of 8	NP_001411343.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SNTA1	ENST00000217381.3	TSL:1 MANE Select	c.828G>A	p.Lys276Lys	synonymous	Exon 4 of 8	ENSP00000217381.2	Q13424-1
	SNTA1	ENST00000953204.1		c.951G>A	p.Lys317Lys	synonymous	Exon 5 of 9	ENSP00000623263.1
	SNTA1	ENST00000953205.1		c.897G>A	p.Lys299Lys	synonymous	Exon 5 of 9	ENSP00000623264.1

Frequencies

GnomAD3 genomes AF: 0.0101 AC: 1532 AN: 152194 Hom.: 15 Cov.: 32

Gnomad AFR AF: 0.00256

Gnomad AMI AF: 0.00659

Gnomad AMR AF: 0.00674

Gnomad ASJ AF: 0.00634

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.0164

Gnomad FIN AF: 0.00358

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0169

Gnomad OTH AF: 0.0110

GnomAD2 exomes AF: 0.0105 AC: 2641 AN: 251106 AF XY: 0.0109

Gnomad AFR exome AF: 0.00289

Gnomad AMR exome AF: 0.00471

Gnomad ASJ exome AF: 0.00526

Gnomad EAS exome AF: 0.000163

Gnomad FIN exome AF: 0.00379

Gnomad NFE exome AF: 0.0152

Gnomad OTH exome AF: 0.00979

GnomAD4 exome AF: 0.0152 AC: 22288 AN: 1461652 Hom.: 212 Cov.: 33 AF XY: 0.0154 AC XY: 11171 AN XY: 727134

African (AFR) AF: 0.00236 AC: 79 AN: 33480

American (AMR) AF: 0.00526 AC: 235 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.00593 AC: 155 AN: 26136

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.0159 AC: 1370 AN: 86254

European-Finnish (FIN) AF: 0.00470 AC: 250 AN: 53228

Middle Eastern (MID) AF: 0.00780 AC: 45 AN: 5766

European-Non Finnish (NFE) AF: 0.0174 AC: 19325 AN: 1111978

Other (OTH) AF: 0.0137 AC: 828 AN: 60392

GnomAD4 genome AF: 0.0101 AC: 1531 AN: 152312 Hom.: 15 Cov.: 32 AF XY: 0.00937 AC XY: 698 AN XY: 74484

African (AFR) AF: 0.00255 AC: 106 AN: 41580

American (AMR) AF: 0.00673 AC: 103 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00634 AC: 22 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5174

South Asian (SAS) AF: 0.0162 AC: 78 AN: 4820

European-Finnish (FIN) AF: 0.00358 AC: 38 AN: 10622

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.0170 AC: 1153 AN: 68022

Other (OTH) AF: 0.0109 AC: 23 AN: 2114

Alfa AF: 0.0154 Hom.: 51

Bravo AF: 0.00983

Asia WGS AF: 0.00491 AC: 17 AN: 3478

EpiCase AF: 0.0173

EpiControl AF: 0.0151

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	2	Long QT syndrome 12 (2)
-	-	1	Cardiovascular phenotype (1)
-	1	-	Congenital long QT syndrome (1)
-	-	1	Long QT syndrome (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.43
CADD	Benign	7.5
DANN	Benign	0.45
PhyloP100		0.27
Mutation Taster		=100/0	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: rs35938843; hg19: chr20-32000462; COSMIC: COSV54128319;