2-54665986-C-A

Position:

• chr2-54665986-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2 PP2 PP5_Moderate

The NM_003128.3(SPTBN1):​c.6731C>A​(p.Ala2244Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely 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: 2.04

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 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• 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.
• PP5: Variant 2-54665986-C-A is Pathogenic according to our data. Variant chr2-54665986-C-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1318838.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SPTBN1	NM_003128.3	c.6731C>A	p.Ala2244Asp	missense_variant	34/36	ENST00000356805.9	NP_003119.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SPTBN1	ENST00000356805.9	c.6731C>A	p.Ala2244Asp	missense_variant	34/36	1	NM_003128.3	ENSP00000349259.4
SPTBN1	ENST00000615901.4	c.6737C>A	p.Ala2246Asp	missense_variant	36/38	5
SPTBN1	ENST00000467371.1	n.1863C>A		non_coding_transcript_exon_variant	2/4	2
SPTBN1-AS2	ENST00000626206.1	n.223-1145G>T		intron_variant		5

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

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Aug 13, 2022

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; In silico analysis suggests this variant may impact gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown.; Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.45
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.40
CADD	Pathogenic	29
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.53	D;T
Eigen	Benign	0.034
Eigen_PC	Benign	0.083
FATHMM_MKL	Benign	0.47	N
LIST_S2	Benign	0.85	T;T
M_CAP	Benign	0.0078	T
MetaRNN	Benign	0.22	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.5	L;.
PrimateAI	Uncertain	0.52	T
PROVEAN	Benign	-1.4	N;.
REVEL	Benign	0.11
Sift	Benign	0.13	T;.
Sift4G	Benign	0.18	T;T
Polyphen		0.0070	B;.
Vest4		0.51
MutPred		0.39		Gain of disorder (P = 0.0641);.;
MVP		0.30
MPC		0.70
ClinPred		0.74	D
GERP RS		4.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.2
Varity_R		0.35
gMVP		0.27

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.38		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.38		Position offset: 22

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: chr2-54893123;