chr2-54612188-A-T

Variant names:

• chr2-54612188-A-T
• NM_003128.3:c.328A>T

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 7P and 2B. PM1 PM2 PP2 PP3_Moderate BP6_Moderate

The NM_003128.3(SPTBN1):​c.328A>T​(p.Ile110Phe) 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. Variant has been reported in ClinVar as Likely benign (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: SPTBN1 NM_003128.3 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 9.27

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 Uncertain_significance. Variant got 5 ACMG points.

• PM1: In a region_of_interest Actin-binding (size 273) in uniprot entity SPTB2_HUMAN there are 11 pathogenic changes around while only 0 benign (100%) in NM_003128.3
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the SPTBN1 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 13 curated pathogenic missense variants (we use a threshold of 10). The gene has 20 curated benign missense variants. Gene score misZ: 4.5424 (above the threshold of 3.09). Trascript score misZ: 5.885 (above the threshold of 3.09). GenCC associations: The gene is linked to developmental delay, impaired speech, and behavioral abnormalities.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.869
• BP6: Variant 2-54612188-A-T is Benign according to our data. Variant chr2-54612188-A-T is described in ClinVar as [Likely_benign]. Clinvar id is 2920715.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SPTBN1	NM_003128.3	c.328A>T	p.Ile110Phe	missense_variant	Exon 4 of 36	ENST00000356805.9	NP_003119.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SPTBN1	ENST00000356805.9	c.328A>T	p.Ile110Phe	missense_variant	Exon 4 of 36	1	NM_003128.3	ENSP00000349259.4
SPTBN1	ENST00000333896.5	c.289A>T	p.Ile97Phe	missense_variant	Exon 3 of 31	1		ENSP00000334156.5
SPTBN1	ENST00000389980.7	c.328A>T	p.Ile110Phe	missense_variant	Exon 4 of 14	1		ENSP00000374630.3
SPTBN1	ENST00000615901.4	c.328A>T	p.Ile110Phe	missense_variant	Exon 4 of 38	5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Developmental disorder Benign:1

Nov 16, 2023

Department of Genetics, Rouen University Hospital, Normandy Center for Genomic and Personalized Medicine

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.44	D
BayesDel_noAF	Pathogenic	0.39
CADD	Pathogenic	26
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.92	D;T;D;.
Eigen	Pathogenic	0.73
Eigen_PC	Pathogenic	0.74
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.95	D;D;D;D
M_CAP	Pathogenic	0.44	D
MetaRNN	Pathogenic	0.87	D;D;D;D
MetaSVM	Pathogenic	0.94	D
MutationAssessor	Benign	0.97	L;.;.;.
PrimateAI	Pathogenic	0.93	D
PROVEAN	Uncertain	-3.8	D;.;D;D
REVEL	Pathogenic	0.82
Sift	Pathogenic	0.0	D;.;D;D
Sift4G	Uncertain	0.050	T;T;T;T
Polyphen		1.0	D;.;.;D
Vest4		0.69
MutPred		0.66		Gain of methylation at R109 (P = 0.0432);Gain of methylation at R109 (P = 0.0432);Gain of methylation at R109 (P = 0.0432);.;
MVP		0.98
MPC		3.3
ClinPred		0.99	D
GERP RS		5.3
Varity_R		0.85
gMVP		0.97

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: chr2-54839325;