2-54558889-T-C

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PVS1PM2

The NM_178313.3(SPTBN1):​c.109+2T>C variant causes a splice donor, intron change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (no stars).

Frequency

Genomes: not found (cov: 32)

Consequence

SPTBN1
NM_178313.3 splice_donor, intron

Scores

3
4
Splicing: ADA: 0.7805
2

Clinical Significance

Uncertain significance no assertion criteria provided U:1

Conservation

PhyloP100: 5.58
Variant links:
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]

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 10 ACMG points.

PVS1
Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, Cryptic splice site detected, with MaxEntScore 5.4, offset of -49, new splice context is: cagGTgcct. Cryptic site results in frameshift change. If cryptic site found is not functional and variant results in exon loss, it results in frameshift change.
PM2
Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
SPTBN1NM_003128.3 linkuse as main transcriptc.148+32323T>C intron_variant ENST00000356805.9 NP_003119.2 Q01082-1B2ZZ89

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
SPTBN1ENST00000356805.9 linkuse as main transcriptc.148+32323T>C intron_variant 1 NM_003128.3 ENSP00000349259.4 Q01082-1
SPTBN1ENST00000333896.5 linkuse as main transcriptc.109+2T>C splice_donor_variant, intron_variant 1 ENSP00000334156.5 Q01082-3
SPTBN1ENST00000389980.7 linkuse as main transcriptc.148+32323T>C intron_variant 1 ENSP00000374630.3 F8W6C1
SPTBN1ENST00000615901.4 linkuse as main transcriptc.148+32323T>C intron_variant 5 A0A087WUZ3

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
31
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: no assertion criteria provided
LINK: link

Submissions by phenotype

SPTBN1-related disorder Uncertain:1
Uncertain significance, no assertion criteria providedclinical testingPreventionGenetics, part of Exact SciencesMay 17, 2024The SPTBN1 c.109+2T>C variant is predicted to disrupt the GT donor site and interfere with normal splicing. This variant is referred to as a deep intronic variant c.148+32323T>C with the primary transcript NM_003128. To our knowledge, this variant has not been reported in the literature or in a large population database, indicating this variant is rare. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Benign
-0.11
T
BayesDel_noAF
Benign
-0.39
CADD
Benign
22
DANN
Uncertain
0.99
Eigen
Uncertain
0.33
Eigen_PC
Uncertain
0.41
FATHMM_MKL
Benign
0.59
D
MutationTaster
Benign
1.0
D;D
GERP RS
5.4

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Benign
0.78
dbscSNV1_RF
Benign
0.71
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: chr2-54786026; API