Genetic Variant SPTAN1:p.His2138Gln (chr9-128626525-C-A) – ACMG Classification: Uncertain_significance (4 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The ENST00000372739.7(SPTAN1):c.6414C>A(p.His2138Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. H2138H) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 33)

Consequence

SPTAN1
ENST00000372739.7 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -2.00

Publications

0 publications found

Variant links:

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: G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine
genetic developmental and epileptic encephalopathy
Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
infantile spasms
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

SPTAN1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.92

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000372739.7. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
SPTAN1	NM_001130438.3	MANE Select	c.6414C>A	p.His2138Gln	missense	Exon 49 of 57	NP_001123910.1
SPTAN1	NM_001375318.1		c.6450C>A	p.His2150Gln	missense	Exon 50 of 59	NP_001362247.1
SPTAN1	NM_001375310.1		c.6414C>A	p.His2138Gln	missense	Exon 49 of 58	NP_001362239.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
SPTAN1	ENST00000372739.7	TSL:1 MANE Select	c.6414C>A	p.His2138Gln	missense	Exon 49 of 57	ENSP00000361824.4
SPTAN1	ENST00000372731.8	TSL:1	c.6399C>A	p.His2133Gln	missense	Exon 48 of 56	ENSP00000361816.4
SPTAN1	ENST00000358161.9	TSL:1	c.6339C>A	p.His2113Gln	missense	Exon 47 of 55	ENSP00000350882.6

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000398

AC:

AN:

251300

AF XY:

0.00

show subpopulations

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

Cov.:

GnomAD4 genome

Cov.:

ExAC

AF:

0.00000824

AC:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.99

BayesDel_addAF

Uncertain

0.020

BayesDel_noAF

Uncertain

-0.040

CADD

Benign

(source)

DANN

Benign

0.97

DEOGEN2

Uncertain

0.45

Eigen

Benign

-0.63

Eigen_PC

Benign

-0.94

FATHMM_MKL

Benign

0.20

LIST_S2

Pathogenic

0.98

M_CAP

Benign

0.064

MetaRNN

Pathogenic

0.92

MetaSVM

Uncertain

0.096

MutationAssessor

Uncertain

2.6

PhyloP100

-2.0

PrimateAI

Pathogenic

0.83

PROVEAN

Pathogenic

-6.2

REVEL

Uncertain

0.43

Sift

Benign

0.042

Sift4G

Uncertain

0.059

Polyphen

1.0

Vest4

0.87

MutPred

0.85

Gain of loop (P = 0.1081)

MVP

0.71

MPC

1.6

ClinPred

0.91

GERP RS

-9.8

Varity_R

0.54

gMVP

0.92

Mutation Taster

=44/56

disease causing

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over