rs141980692

Variant names:

• chr9-128633219-G-A
• rs141980692
• NM_001130438.3:c.7319G>A

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS1

The NM_001130438.3(SPTAN1):​c.7319G>A​(p.Arg2440Gln) variant causes a missense change. The variant allele was found at a frequency of 0.000393 in 1,613,974 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00032 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00040 (1 hom.)
• Consequence: SPTAN1 NM_001130438.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 5.39
• Publications: 5 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 -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.041474193).
• BP6: Variant 9-128633219-G-A is Benign according to our data. Variant chr9-128633219-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 207310.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.000315 (48/152220) while in subpopulation SAS AF = 0.00083 (4/4820). AF 95% confidence interval is 0.000283. There are 0 homozygotes in GnomAd4. There are 16 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

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.7319G>A	p.Arg2440Gln	missense	Exon 57 of 57	NP_001123910.1	Q13813-2
	SPTAN1	NM_001375318.1		c.7418G>A	p.Arg2473Gln	missense	Exon 59 of 59	NP_001362247.1
	SPTAN1	NM_001375310.1		c.7406G>A	p.Arg2469Gln	missense	Exon 58 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.7319G>A	p.Arg2440Gln	missense	Exon 57 of 57	ENSP00000361824.4	Q13813-2
	SPTAN1	ENST00000372731.8	TSL:1	c.7304G>A	p.Arg2435Gln	missense	Exon 56 of 56	ENSP00000361816.4	Q13813-1
	SPTAN1	ENST00000358161.9	TSL:1	c.7244G>A	p.Arg2415Gln	missense	Exon 55 of 55	ENSP00000350882.6	Q13813-3

Frequencies

GnomAD3 genomes AF: 0.000316 AC: 48 AN: 152102 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.000829

Gnomad FIN AF: 0.000659

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000353

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000395 AC: 99 AN: 250938 AF XY: 0.000479

Gnomad AFR exome AF: 0.0000617

Gnomad AMR exome AF: 0.000579

Gnomad ASJ exome AF: 0.000794

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000463

Gnomad NFE exome AF: 0.000362

Gnomad OTH exome AF: 0.000489

GnomAD4 exome AF: 0.000401 AC: 586 AN: 1461754 Hom.: 1 Cov.: 32 AF XY: 0.000413 AC XY: 300 AN XY: 727186

African (AFR) AF: 0.0000896 AC: 3 AN: 33480

American (AMR) AF: 0.000581 AC: 26 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.000459 AC: 12 AN: 26136

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39698

South Asian (SAS) AF: 0.000475 AC: 41 AN: 86258

European-Finnish (FIN) AF: 0.000506 AC: 27 AN: 53308

Middle Eastern (MID) AF: 0.000693 AC: 4 AN: 5768

European-Non Finnish (NFE) AF: 0.000407 AC: 453 AN: 1111998

Other (OTH) AF: 0.000315 AC: 19 AN: 60394

GnomAD4 genome AF: 0.000315 AC: 48 AN: 152220 Hom.: 0 Cov.: 33 AF XY: 0.000215 AC XY: 16 AN XY: 74432

African (AFR) AF: 0.000120 AC: 5 AN: 41528

American (AMR) AF: 0.000196 AC: 3 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.00115 AC: 4 AN: 3468

East Asian (EAS) AF: 0.000194 AC: 1 AN: 5164

South Asian (SAS) AF: 0.000830 AC: 4 AN: 4820

European-Finnish (FIN) AF: 0.000659 AC: 7 AN: 10616

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.000353 AC: 24 AN: 68018

Other (OTH) AF: 0.00 AC: 0 AN: 2112

Alfa AF: 0.000351 Hom.: 0

Bravo AF: 0.000276

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.000778 AC: 3

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.000371 AC: 45

EpiCase AF: 0.000545

EpiControl AF: 0.000296

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	2	Developmental and epileptic encephalopathy, 5 (2)
-	-	1	Developmental and epileptic encephalopathy (1)
-	-	1	Inborn genetic diseases (1)
-	-	1	Lymphedema (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.39	T
BayesDel_noAF	Benign	-0.44
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Benign	0.10	T
Eigen	Benign	-0.0049
Eigen_PC	Benign	0.17
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Benign	0.018	T
MetaRNN	Benign	0.041	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.55	N
PhyloP100		5.4
PrimateAI	Uncertain	0.70	T
PROVEAN	Benign	-0.69	N
REVEL	Benign	0.068
Sift	Benign	0.14	T
Sift4G	Benign	0.075	T
Polyphen		0.77	P
Vest4		0.38
MVP		0.40
MPC		0.91
ClinPred		0.025	T
GERP RS		4.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.14
gMVP		0.17
Mutation Taster		=89/11	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		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: rs141980692; hg19: chr9-131395498;