2-54599202-A-T

Variant names:

• chr2-54599202-A-T
• rs1553338193
• NM_003128.3:c.259A>T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_003128.3(SPTBN1):​c.259A>T​(p.Met87Leu) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: SPTBN1 NM_003128.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.08
• Publications: 0 publications found

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]

SPTBN1 Gene-Disease associations (from GenCC):

• developmental delay, impaired speech, and behavioral abnormalities

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: ClinGen, Labcorp Genetics (formerly Invitae), G2P, PanelApp Australia

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003128.3. 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
	SPTBN1	NM_003128.3	MANE Select	c.259A>T	p.Met87Leu	missense	Exon 3 of 36	NP_003119.2	Q01082-1
	SPTBN1	NM_178313.3		c.220A>T	p.Met74Leu	missense	Exon 2 of 31	NP_842565.2	Q01082-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SPTBN1	ENST00000356805.9	TSL:1 MANE Select	c.259A>T	p.Met87Leu	missense	Exon 3 of 36	ENSP00000349259.4	Q01082-1
	SPTBN1	ENST00000333896.5	TSL:1	c.220A>T	p.Met74Leu	missense	Exon 2 of 31	ENSP00000334156.5	Q01082-3
	SPTBN1	ENST00000389980.7	TSL:1	c.259A>T	p.Met87Leu	missense	Exon 3 of 14	ENSP00000374630.3	F8W6C1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.28
BayesDel_addAF	Pathogenic	0.29	D
BayesDel_noAF	Pathogenic	0.18
CADD	Pathogenic	27
DANN	Uncertain	0.98
DEOGEN2	Pathogenic	0.87	D
Eigen	Benign	0.12
Eigen_PC	Uncertain	0.31
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Uncertain	0.92	D
M_CAP	Benign	0.039	D
MetaRNN	Uncertain	0.58	D
MetaSVM	Uncertain	0.51	D
MutationAssessor	Benign	-0.075	N
PhyloP100		6.1
PrimateAI	Pathogenic	0.85	D
PROVEAN	Uncertain	-2.4	N
REVEL	Uncertain	0.59
Sift	Benign	0.036	D
Sift4G	Benign	0.15	T
Polyphen		0.65	P
Vest4		0.50
MutPred		0.53		Loss of MoRF binding (P = 0.105)
MVP		0.97
MPC		1.7
ClinPred		0.85	D
GERP RS		5.7
Varity_R		0.52
gMVP		0.88
Mutation Taster		=51/49	polymorphism

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

Other links and lift over

dbSNP: rs1553338193; hg19: chr2-54826339;