chr9-128625858-C-T

Variant names:

• chr9-128625858-C-T
• rs150902677
• NM_001130438.3:c.6159C>T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_001130438.3(SPTAN1):​c.6159C>T​(p.His2053His) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00033 in 1,614,192 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00047 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00032 (6 hom.)
• Consequence: SPTAN1 NM_001130438.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.561
• Publications: 1 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: 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

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.58).
• BP6: Variant 9-128625858-C-T is Benign according to our data. Variant chr9-128625858-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 139307.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.561 with no splicing effect.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.000473 (72/152306) while in subpopulation AMR AF = 0.000261 (4/15304). AF 95% confidence interval is 0.000135. There are 1 homozygotes in GnomAd4. There are 33 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 72 AD gene.

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.6159C>T	p.His2053His	synonymous	Exon 48 of 57	NP_001123910.1
	SPTAN1	NM_001375318.1		c.6195C>T	p.His2065His	synonymous	Exon 49 of 59	NP_001362247.1
	SPTAN1	NM_001375310.1		c.6159C>T	p.His2053His	synonymous	Exon 48 of 58	NP_001362239.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SPTAN1	ENST00000372739.7	TSL:1 MANE Select	c.6159C>T	p.His2053His	synonymous	Exon 48 of 57	ENSP00000361824.4
	SPTAN1	ENST00000372731.8	TSL:1	c.6144C>T	p.His2048His	synonymous	Exon 47 of 56	ENSP00000361816.4
	SPTAN1	ENST00000358161.9	TSL:1	c.6084C>T	p.His2028His	synonymous	Exon 46 of 55	ENSP00000350882.6

Frequencies

GnomAD3 genomes AF: 0.000460 AC: 70 AN: 152188 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.0127

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000220

Gnomad OTH AF: 0.00143

GnomAD2 exomes AF: 0.000672 AC: 169 AN: 251488 AF XY: 0.000706

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.0128

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000272

Gnomad OTH exome AF: 0.00130

GnomAD4 exome AF: 0.000315 AC: 461 AN: 1461886 Hom.: 6 Cov.: 32 AF XY: 0.000327 AC XY: 238 AN XY: 727244

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

American (AMR) AF: 0.0000224 AC: 1 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0110 AC: 287 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000348 AC: 3 AN: 86258

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

Middle Eastern (MID) AF: 0.00121 AC: 7 AN: 5768

European-Non Finnish (NFE) AF: 0.0000899 AC: 100 AN: 1112008

Other (OTH) AF: 0.000993 AC: 60 AN: 60396

GnomAD4 genome AF: 0.000473 AC: 72 AN: 152306 Hom.: 1 Cov.: 32 AF XY: 0.000443 AC XY: 33 AN XY: 74472

African (AFR) AF: 0.0000481 AC: 2 AN: 41560

American (AMR) AF: 0.000261 AC: 4 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.0127 AC: 44 AN: 3470

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5172

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.000220 AC: 15 AN: 68034

Other (OTH) AF: 0.00237 AC: 5 AN: 2114

Alfa AF: 0.000863 Hom.: 0

Bravo AF: 0.000419

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.000491

EpiControl AF: 0.000296

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.58
CADD	Benign	7.3
DANN	Benign	0.38
PhyloP100		0.56
PromoterAI		-0.0090	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs150902677; hg19: chr9-131388137; COSMIC: COSV63990211; COSMIC: COSV63990211;