chr2-54666036-G-C

Variant names:

• chr2-54666036-G-C
• NM_003128.3:c.6781G>C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2 PP2 BP4_Moderate

The NM_003128.3(SPTBN1):​c.6781G>C​(p.Val2261Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,652 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: SPTBN1 NM_003128.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.413

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-AS2 (HGNC:40563): (SPTBN1 antisense RNA 2)

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• 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.
• BP4: Computational evidence support a benign effect (MetaRNN=0.1482935).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SPTBN1	NM_003128.3	c.6781G>C	p.Val2261Leu	missense_variant	Exon 34 of 36	ENST00000356805.9	NP_003119.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SPTBN1	ENST00000356805.9	c.6781G>C	p.Val2261Leu	missense_variant	Exon 34 of 36	1	NM_003128.3	ENSP00000349259.4
SPTBN1	ENST00000615901.4	c.6787G>C	p.Val2263Leu	missense_variant	Exon 36 of 38	5
SPTBN1	ENST00000467371.1	n.1913G>C		non_coding_transcript_exon_variant	Exon 2 of 4	2
SPTBN1-AS2	ENST00000626206.1	n.223-1195C>G		intron_variant	Intron 1 of 3	5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461652 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 727132

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Mar 10, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.6781G>C (p.V2261L) alteration is located in exon 34 (coding exon 33) of the SPTBN1 gene. This alteration results from a G to C substitution at nucleotide position 6781, causing the valine (V) at amino acid position 2261 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.075
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.67
CADD	Benign	0.69
DANN	Benign	0.85
DEOGEN2	Benign	0.41	T;T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.22	N
LIST_S2	Benign	0.70	T;T
M_CAP	Benign	0.0043	T
MetaRNN	Benign	0.15	T;T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	0.20	N;.
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-0.52	N;.
REVEL	Benign	0.11
Sift	Benign	0.25	T;.
Sift4G	Benign	0.67	T;T
Polyphen		0.0	B;.
Vest4		0.11
MutPred		0.37		Loss of methylation at K2258 (P = 0.0705);.;
MVP		0.35
MPC		0.35
ClinPred		0.028	T
GERP RS		-8.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.064
gMVP		0.10

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: chr2-54893173;