9-128625889-G-T

Variant names:

• chr9-128625889-G-T
• rs201411901
• NM_001130438.3:c.6190G>T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001130438.3(SPTAN1):​c.6190G>T​(p.Ala2064Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,890 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A2064T) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: SPTAN1 NM_001130438.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 9.59
• Publications: 7 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: Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine, G2P, Ambry Genetics
• genetic developmental and epileptic encephalopathy

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• infantile spasms

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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.6190G>T	p.Ala2064Ser	missense	Exon 48 of 57	NP_001123910.1	Q13813-2
	SPTAN1	NM_001375318.1		c.6226G>T	p.Ala2076Ser	missense	Exon 49 of 59	NP_001362247.1
	SPTAN1	NM_001375310.1		c.6190G>T	p.Ala2064Ser	missense	Exon 48 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.6190G>T	p.Ala2064Ser	missense	Exon 48 of 57	ENSP00000361824.4	Q13813-2
	SPTAN1	ENST00000372731.8	TSL:1	c.6175G>T	p.Ala2059Ser	missense	Exon 47 of 56	ENSP00000361816.4	Q13813-1
	SPTAN1	ENST00000358161.9	TSL:1	c.6115G>T	p.Ala2039Ser	missense	Exon 46 of 55	ENSP00000350882.6	Q13813-3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251456 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461890 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 727248

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

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

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53416

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1112012

Other (OTH) AF: 0.00 AC: 0 AN: 60396

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.085
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.26
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.092	T
Eigen	Uncertain	0.45
Eigen_PC	Uncertain	0.55
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.91	D
M_CAP	Benign	0.027	D
MetaRNN	Uncertain	0.51	D
MetaSVM	Benign	-0.81	T
MutationAssessor	Uncertain	2.1	M
PhyloP100		9.6
PrimateAI	Uncertain	0.59	T
PROVEAN	Benign	-0.35	N
REVEL	Benign	0.20
Sift	Benign	0.038	D
Sift4G	Benign	0.28	T
Polyphen		0.44	B
Vest4		0.61
MutPred		0.34		Gain of phosphorylation at A2059 (P = 0.0348)
MVP		0.47
MPC		0.88
ClinPred		0.63	D
GERP RS		5.3
PromoterAI		0.033	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.19
gMVP		0.16
Mutation Taster		=74/26	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: rs201411901; hg19: chr9-131388168;