14-64753580-G-T

Variant names:

• chr14-64753580-G-T
• rs199938084
• NM_001355436.2:c.6559C>A

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_001355436.2(SPTB):​c.6559C>A​(p.Arg2187Ser) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,292 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic 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: SPTB NM_001355436.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.50

Genes affected

SPTB (HGNC:11274): (spectrin beta, erythrocytic) This locus encodes a member of the spectrin gene family. Spectrin proteins, along with ankyrin, play a role in cell membrane organization and stability. The protein encoded by this locus functions in stability of erythrocyte membranes, and mutations in this gene have been associated with spherocytosis type 2, hereditary elliptocytosis, and neonatal hemolytic anemia. Alternatively spliced transcript variants have been described. [provided by RefSeq, Nov 2009]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.836

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SPTB	NM_001355436.2	c.6559C>A	p.Arg2187Ser	missense_variant	Exon 33 of 36	ENST00000644917.1	NP_001342365.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SPTB	ENST00000644917.1	c.6559C>A	p.Arg2187Ser	missense_variant	Exon 33 of 36		NM_001355436.2	ENSP00000495909.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461292 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 726932

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

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Uncertain	0.037	T
BayesDel_noAF	Benign	-0.18
CADD	Uncertain	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.30	.;.;.;T
Eigen	Pathogenic	0.76
Eigen_PC	Pathogenic	0.69
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Uncertain	0.97	.;.;D;D
M_CAP	Uncertain	0.15	D
MetaRNN	Pathogenic	0.84	D;D;D;D
MetaSVM	Uncertain	0.32	D
PrimateAI	Uncertain	0.76	T
PROVEAN	Pathogenic	-4.8	D;.;D;D
REVEL	Uncertain	0.39
Sift	Pathogenic	0.0	D;.;D;D
Sift4G	Pathogenic	0.0010	D;.;D;D
Vest4		0.77
MutPred		0.74		Loss of catalytic residue at R2187 (P = 0.0091);Loss of catalytic residue at R2187 (P = 0.0091);Loss of catalytic residue at R2187 (P = 0.0091);.;
MVP		0.30
MPC		0.80
ClinPred		1.0	D
GERP RS		4.6
gMVP		0.85

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

LitVar

Other links and lift over

dbSNP: rs199938084; hg19: chr14-65220298;