2-54599119-C-T

Position:

• chr2-54599119-C-T

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PS1_Moderate PM1 PM2 PM5 PP2 PP3_Moderate PP5_Moderate

The NM_003128.3(SPTBN1):​c.176C>T​(p.Thr59Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 13/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely pathogenicin UniProt. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T59S) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SPTBN1 NM_003128.3 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 7.86

Genes affected

SPTBN1 (HGNC:11275): (spectrin beta, non-erythrocytic 1) Spectrin is an actin crosslinking and molecular scaffold protein that links the plasma membrane to the actin cytoskeleton, and functions in the determination of cell shape, arrangement of transmembrane proteins, and organization of organelles. It is composed of two antiparallel dimers of alpha- and beta- subunits. This gene is one member of a family of beta-spectrin genes. The encoded protein contains an N-terminal actin-binding domain, and 17 spectrin repeats which are involved in dimer formation. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Pathogenic. Variant got 13 ACMG points.

• PS1: Transcript NM_003128.3 (SPTBN1) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in UniProt
• PM1: In a region_of_interest Actin-binding (size 273) in uniprot entity SPTB2_HUMAN there are 21 pathogenic changes around while only 1 benign (95%) in NM_003128.3
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr2-54599119-C-G is described in ClinVar as [Pathogenic]. Clinvar id is 2438401.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), SPTBN1. . Gene score misZ 4.5424 (greater than the threshold 3.09). Trascript score misZ 5.885 (greater than threshold 3.09). GenCC has associacion of gene with developmental delay, impaired speech, and behavioral abnormalities.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.939
• PP5: Variant 2-54599119-C-T is Pathogenic according to our data. Variant chr2-54599119-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 2674610.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SPTBN1	NM_003128.3	c.176C>T	p.Thr59Ile	missense_variant	3/36	ENST00000356805.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SPTBN1	ENST00000356805.9	c.176C>T	p.Thr59Ile	missense_variant	3/36	1	NM_003128.3	P1
SPTBN1	ENST00000333896.5	c.137C>T	p.Thr46Ile	missense_variant	2/31	1
SPTBN1	ENST00000389980.7	c.176C>T	p.Thr59Ile	missense_variant	3/14	1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Developmental delay, impaired speech, and behavioral abnormalities Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Division Of Personalized Genomic Medicine, Columbia University Irving Medical Center

Sep 02, 2021

The c.176C>T variant is a heterozygous single base pair substitution at nucleotide 176 in exon 3 of 36 of the SPTBN1 gene, resulting in a substitution of a highly conserved threonine at amino acid position 59 to a isoleucine (p.Thr59Ile). This variant is absent from the gnomAD database, indicating it is not a common benign occurrence in the populations represented in these databases. This variant is predicted to damage protein structure and/or function based on in silico algorithms (PolyPhen2, SIFT, DANN). The SPTBN1 gene encodes neuronal beta-II spectrin, the most abundant beta-spectrin in the brain and a subunit of spectrin. Spectrins are components of the cytoskeleton and allow proper localization of essential membrane proteins, signal transduction and cellular scaffolding through the binding of cytoskeletal elements and the plasma membrane (PMID: 33847457). The threonine at position 59 falls in the calponin homology domain 1 (CH1) conserved region, which is essential for proper interaction with actin (PMID: 34211179). Heterozygous pathogenic variants in SPTBN1 have recently been linked to developmental delay, impaired speech, and behavioral abnormalities. Both missense and truncating variants have been reported to be associated with this phenotype (PMIDs: 33847457, 34211179). Functional studies on the p.Thr59Ile variant were completed by Cousin et al (PMID: 34211179). In vitro functional expression studies in HEK293 cells transfected with the p.Thr59Ile variant demonstrated reduced protein levels relative to control. In addition, a cosedimentation assay demonstrated that the p.Thr59Ile variant reduced F-actin binding. Studies of cortical neurons derived from Sptbn1-null mice showed impaired organization of the axon initial segment (AIS) with reduced axonal growth, dendritic abnormalities, and aberrant lysosome dynamics. These defects could not be fully rescued by expression of the protein containing the p.Thr59Ile variant, suggesting pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.58	D
BayesDel_noAF	Pathogenic	0.60
CADD	Pathogenic	31
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.98	D;T;D;.
Eigen	Pathogenic	0.98
Eigen_PC	Pathogenic	0.93
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Pathogenic	0.98	D;D;D;D
M_CAP	Pathogenic	0.67	D
MetaRNN	Pathogenic	0.94	D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.3	M;.;.;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.90	D
PROVEAN	Pathogenic	-5.4	D;.;D;D
REVEL	Pathogenic	0.91
Sift	Pathogenic	0.0	D;.;D;D
Sift4G	Pathogenic	0.0	D;D;D;D
Polyphen		1.0	D;.;.;D
Vest4		0.98
MutPred		0.75		Loss of disorder (P = 0.0581);Loss of disorder (P = 0.0581);Loss of disorder (P = 0.0581);.;
MVP		1.0
MPC		2.7
ClinPred		1.0	D
GERP RS		5.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.84
gMVP		0.99

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr2-54826256;