rs139799727

Positions:

• chr9-128625810-C-T

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 0P and 15B. BP4_Moderate BP6_Very_Strong BP7 BS2

The NM_001130438.3(SPTAN1):​c.6111C>T​(p.Gly2037=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00261 in 1,614,174 control chromosomes in the GnomAD database, including 8 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0017 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0027 (8 hom.)
• Consequence: SPTAN1 NM_001130438.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 0.644

Genes affected

SPTAN1 (HGNC:11273): (spectrin alpha, non-erythrocytic 1) Spectrins are a family of filamentous cytoskeletal proteins that function as essential scaffold proteins that stabilize the plasma membrane and organize intracellular organelles. Spectrins are composed of alpha and beta dimers that associate to form tetramers linked in a head-to-head arrangement. This gene encodes an alpha spectrin that is specifically expressed in nonerythrocytic cells. The encoded protein has been implicated in other cellular functions including DNA repair and cell cycle regulation. Mutations in this gene are the cause of early infantile epileptic encephalopathy-5. Alternate splicing results in multiple transcript variants.[provided by RefSeq, Sep 2010]

ACMG classification

Verdict is Benign. Variant got -15 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.35).
• BP6: Variant 9-128625810-C-T is Benign according to our data. Variant chr9-128625810-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 139306.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.644 with no splicing effect.
• BS2: High AC in GnomAd4 at 265 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SPTAN1	NM_001130438.3	c.6111C>T	p.Gly2037=	synonymous_variant	48/57	ENST00000372739.7	NP_001123910.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SPTAN1	ENST00000372739.7	c.6111C>T	p.Gly2037=	synonymous_variant	48/57	1	NM_001130438.3	ENSP00000361824	P3

Frequencies

GnomAD3 genomes AF: 0.00173 AC: 264 AN: 152180 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000603

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000916

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00559

Gnomad FIN AF: 0.000188

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00275

Gnomad OTH AF: 0.00382

GnomAD3 exomes AF: 0.00232 AC: 584 AN: 251428 Hom.: 2 AF XY: 0.00257 AC XY: 349 AN XY: 135892

Gnomad AFR exome AF: 0.000431

Gnomad AMR exome AF: 0.000954

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00735

Gnomad FIN exome AF: 0.000277

Gnomad NFE exome AF: 0.00266

Gnomad OTH exome AF: 0.00147

GnomAD4 exome AF: 0.00270 AC: 3944 AN: 1461876 Hom.: 8 Cov.: 32 AF XY: 0.00281 AC XY: 2045 AN XY: 727240

Gnomad4 AFR exome AF: 0.000269

Gnomad4 AMR exome AF: 0.000961

Gnomad4 ASJ exome AF: 0.0000765

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.00738

Gnomad4 FIN exome AF: 0.000393

Gnomad4 NFE exome AF: 0.00275

Gnomad4 OTH exome AF: 0.00242

GnomAD4 genome AF: 0.00174 AC: 265 AN: 152298 Hom.: 0 Cov.: 32 AF XY: 0.00173 AC XY: 129 AN XY: 74462

Gnomad4 AFR AF: 0.000602

Gnomad4 AMR AF: 0.000915

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00580

Gnomad4 FIN AF: 0.000188

Gnomad4 NFE AF: 0.00275

Gnomad4 OTH AF: 0.00378

Alfa AF: 0.00184 Hom.: 0

Bravo AF: 0.00148

Asia WGS AF: 0.00231 AC: 8 AN: 3478

EpiCase AF: 0.00267

EpiControl AF: 0.00243

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Aug 02, 2016	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 07, 2014	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Likely benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Sep 18, 2018	- -

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jun 01, 2024	SPTAN1: BP4, BP7, BS1 -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Dec 20, 2017	- -

Inborn genetic diseases Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 06, 2016

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Early infantile epileptic encephalopathy with suppression bursts Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

Developmental and epileptic encephalopathy, 5 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 15, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.35
CADD	Benign	12
DANN	Benign	0.64

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs139799727; hg19: chr9-131388089;