2-54665986-C-T

Variant names:

• chr2-54665986-C-T
• rs956588950
• NM_003128.3:c.6731C>T

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 2P and 6B. PM5 BP4_Moderate BS2

The NM_003128.3(SPTBN1):​c.6731C>T​(p.Ala2244Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000149 in 1,613,996 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A2244D) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000015 (0 hom.)
• Consequence: SPTBN1 NM_003128.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.04
• 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-AS2 (HGNC:40563): (SPTBN1 antisense RNA 2)

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• PM5: Other missense variant is known to change same aminoacid residue: 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.
• BP4: Computational evidence support a benign effect (MetaRNN=0.20475993).
• BS2: High AC in GnomAdExome4 at 22 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SPTBN1	NM_003128.3	c.6731C>T	p.Ala2244Val	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.6731C>T	p.Ala2244Val	missense_variant	Exon 34 of 36	1	NM_003128.3	ENSP00000349259.4
SPTBN1	ENST00000467371.1	n.1863C>T		non_coding_transcript_exon_variant	Exon 2 of 4	2
SPTBN1-AS2	ENST00000626206.1	n.223-1145G>A		intron_variant	Intron 1 of 3	5

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152136 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000795 AC: 2 AN: 251432 AF XY: 0.0000147

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000879

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.0000150 AC: 22 AN: 1461860 Hom.: 0 Cov.: 30 AF XY: 0.0000138 AC XY: 10 AN XY: 727236

African (AFR) AF: 0.00 AC: 0 AN: 33476

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00 AC: 0 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53416

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.0000180 AC: 20 AN: 1111992

Other (OTH) AF: 0.0000331 AC: 2 AN: 60396

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152136 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74316

African (AFR) AF: 0.00 AC: 0 AN: 41432

American (AMR) AF: 0.00 AC: 0 AN: 15260

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5198

South Asian (SAS) AF: 0.00 AC: 0 AN: 4818

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10600

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68038

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.0000434 Hom.: 0

Bravo AF: 0.00000756

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.095
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.47
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.49	T;T
Eigen	Benign	0.17
Eigen_PC	Benign	0.19
FATHMM_MKL	Benign	0.50	N
LIST_S2	Uncertain	0.86	D;D
M_CAP	Benign	0.0059	T
MetaRNN	Benign	0.20	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.3	L;.
PhyloP100		2.0
PrimateAI	Benign	0.44	T
PROVEAN	Benign	-1.4	N;.
REVEL	Benign	0.068
Sift	Uncertain	0.026	D;.
Sift4G	Benign	0.066	T;T
Polyphen		0.48	P;.
Vest4		0.32
MutPred		0.32		Loss of disorder (P = 0.0702);.;
MVP		0.38
MPC		0.61
ClinPred		0.44	T
GERP RS		4.9
Varity_R		0.21
gMVP		0.13
Mutation Taster		=91/9	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		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: rs956588950; hg19: chr2-54893123;