9-128598471-C-T

Variant names:

• chr9-128598471-C-T
• rs2227864
• NM_001130438.3:c.3486C>T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001130438.3(SPTAN1):​c.3486C>T​(p.Leu1162Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.852 in 1,611,482 control chromosomes in the GnomAD database, including 595,480 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. L1162L) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.75 (45441 hom., cov: 31)
  • Exomes 𝑓: 0.86 (550039 hom.)
• Consequence: SPTAN1 NM_001130438.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: 0.0580
• Publications: 25 publications found

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]

SPTAN1 Gene-Disease associations (from GenCC):

• developmental and epileptic encephalopathy, 5

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: PanelApp Australia, Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine, G2P, Ambry Genetics
• genetic developmental and epileptic encephalopathy

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• neuronopathy, distal hereditary motor, autosomal dominant 11

  Inheritance: AD Classification: STRONG Submitted by: PanelApp Australia
• spastic paraplegia 91, autosomal dominant, with or without cerebellar ataxia

  Inheritance: AD Classification: STRONG Submitted by: PanelApp Australia
• infantile spasms

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• hereditary spastic paraplegia

  Inheritance: AR Classification: LIMITED Submitted by: PanelApp Australia

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.69).
• BP6: Variant 9-128598471-C-T is Benign according to our data. Variant chr9-128598471-C-T is described in ClinVar as Benign. ClinVar VariationId is 160009.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.058 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.895 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001130438.3. 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
	SPTAN1	NM_001130438.3	MANE Select	c.3486C>T	p.Leu1162Leu	synonymous	Exon 25 of 57	NP_001123910.1	Q13813-2
	SPTAN1	NM_001375318.1		c.3522C>T	p.Leu1174Leu	synonymous	Exon 26 of 59	NP_001362247.1
	SPTAN1	NM_001375310.1		c.3486C>T	p.Leu1162Leu	synonymous	Exon 25 of 58	NP_001362239.1	A0A994J6W3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SPTAN1	ENST00000372739.7	TSL:1 MANE Select	c.3486C>T	p.Leu1162Leu	synonymous	Exon 25 of 57	ENSP00000361824.4	Q13813-2
	SPTAN1	ENST00000372731.8	TSL:1	c.3486C>T	p.Leu1162Leu	synonymous	Exon 25 of 56	ENSP00000361816.4	Q13813-1
	SPTAN1	ENST00000358161.9	TSL:1	c.3426C>T	p.Leu1142Leu	synonymous	Exon 24 of 55	ENSP00000350882.6	Q13813-3

Frequencies

GnomAD3 genomes AF: 0.750 AC: 113964 AN: 151886 Hom.: 45431 Cov.: 31

Gnomad AFR AF: 0.479

Gnomad AMI AF: 0.959

Gnomad AMR AF: 0.791

Gnomad ASJ AF: 0.895

Gnomad EAS AF: 0.520

Gnomad SAS AF: 0.753

Gnomad FIN AF: 0.821

Gnomad MID AF: 0.826

Gnomad NFE AF: 0.901

Gnomad OTH AF: 0.790

GnomAD2 exomes AF: 0.804 AC: 199258 AN: 247968 AF XY: 0.813

Gnomad AFR exome AF: 0.471

Gnomad AMR exome AF: 0.787

Gnomad ASJ exome AF: 0.894

Gnomad EAS exome AF: 0.505

Gnomad FIN exome AF: 0.819

Gnomad NFE exome AF: 0.898

Gnomad OTH exome AF: 0.835

GnomAD4 exome AF: 0.863 AC: 1258911 AN: 1459478 Hom.: 550039 Cov.: 43 AF XY: 0.862 AC XY: 625553 AN XY: 725832

African (AFR) AF: 0.464 AC: 15512 AN: 33442

American (AMR) AF: 0.790 AC: 34994 AN: 44298

Ashkenazi Jewish (ASJ) AF: 0.892 AC: 23274 AN: 26082

East Asian (EAS) AF: 0.493 AC: 19542 AN: 39636

South Asian (SAS) AF: 0.778 AC: 66626 AN: 85672

European-Finnish (FIN) AF: 0.832 AC: 44378 AN: 53352

Middle Eastern (MID) AF: 0.825 AC: 4662 AN: 5654

European-Non Finnish (NFE) AF: 0.900 AC: 999724 AN: 1111016

Other (OTH) AF: 0.832 AC: 50199 AN: 60326

GnomAD4 genome AF: 0.750 AC: 113998 AN: 152004 Hom.: 45441 Cov.: 31 AF XY: 0.746 AC XY: 55432 AN XY: 74310

African (AFR) AF: 0.478 AC: 19795 AN: 41412

American (AMR) AF: 0.792 AC: 12090 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.895 AC: 3108 AN: 3472

East Asian (EAS) AF: 0.519 AC: 2672 AN: 5148

South Asian (SAS) AF: 0.753 AC: 3629 AN: 4820

European-Finnish (FIN) AF: 0.821 AC: 8684 AN: 10576

Middle Eastern (MID) AF: 0.830 AC: 244 AN: 294

European-Non Finnish (NFE) AF: 0.901 AC: 61233 AN: 67986

Other (OTH) AF: 0.789 AC: 1668 AN: 2114

Alfa AF: 0.846 Hom.: 28168

Bravo AF: 0.735

Asia WGS AF: 0.637 AC: 2215 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	6	not specified (6)
-	-	3	not provided (3)
-	-	1	Developmental and epileptic encephalopathy (1)
-	-	1	Developmental and epileptic encephalopathy, 5 (1)
-	-	1	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.69
CADD	Benign	5.3
DANN	Benign	0.58
PhyloP100		0.058
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=78/22	polymorphism (auto)

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: rs2227864; hg19: chr9-131360750; COSMIC: COSV63985200; COSMIC: COSV63985200;