rs229591

Positions:

• chr14-64793509-T-G

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001355436.2(SPTB):​c.2154A>C​(p.Ile718=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.379 in 1,613,834 control chromosomes in the GnomAD database, including 121,799 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.44 (16184 hom., cov: 32)
  • Exomes 𝑓: 0.37 (105615 hom.)
• Consequence: SPTB NM_001355436.2 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -1.30

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 Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BP6: Variant 14-64793509-T-G is Benign according to our data. Variant chr14-64793509-T-G is described in ClinVar as [Likely_benign]. Clinvar id is 257102.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-64793509-T-G is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-1.3 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.643 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SPTB	NM_001355436.2	c.2154A>C	p.Ile718=	synonymous_variant	14/36	ENST00000644917.1	NP_001342365.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SPTB	ENST00000644917.1	c.2154A>C	p.Ile718=	synonymous_variant	14/36		NM_001355436.2	ENSP00000495909	P1
SPTB	ENST00000389722.7	c.2154A>C	p.Ile718=	synonymous_variant	13/35	2		ENSP00000374372	P1
SPTB	ENST00000389720.4	c.2154A>C	p.Ile718=	synonymous_variant	14/32	5		ENSP00000374370

Frequencies

GnomAD3 genomes AF: 0.440 AC: 66863 AN: 151936 Hom.: 16156 Cov.: 32

Gnomad AFR AF: 0.650

Gnomad AMI AF: 0.481

Gnomad AMR AF: 0.343

Gnomad ASJ AF: 0.431

Gnomad EAS AF: 0.195

Gnomad SAS AF: 0.505

Gnomad FIN AF: 0.345

Gnomad MID AF: 0.430

Gnomad NFE AF: 0.364

Gnomad OTH AF: 0.420

GnomAD3 exomes AF: 0.378 AC: 94946 AN: 250852 Hom.: 19410 AF XY: 0.384 AC XY: 52141 AN XY: 135612

Gnomad AFR exome AF: 0.654

Gnomad AMR exome AF: 0.273

Gnomad ASJ exome AF: 0.434

Gnomad EAS exome AF: 0.183

Gnomad SAS exome AF: 0.504

Gnomad FIN exome AF: 0.336

Gnomad NFE exome AF: 0.372

Gnomad OTH exome AF: 0.380

GnomAD4 exome AF: 0.373 AC: 545365 AN: 1461780 Hom.: 105615 Cov.: 84 AF XY: 0.378 AC XY: 274552 AN XY: 727196

Gnomad4 AFR exome AF: 0.664

Gnomad4 AMR exome AF: 0.285

Gnomad4 ASJ exome AF: 0.445

Gnomad4 EAS exome AF: 0.209

Gnomad4 SAS exome AF: 0.500

Gnomad4 FIN exome AF: 0.337

Gnomad4 NFE exome AF: 0.362

Gnomad4 OTH exome AF: 0.394

GnomAD4 genome AF: 0.440 AC: 66939 AN: 152054 Hom.: 16184 Cov.: 32 AF XY: 0.438 AC XY: 32540 AN XY: 74302

Gnomad4 AFR AF: 0.650

Gnomad4 AMR AF: 0.343

Gnomad4 ASJ AF: 0.431

Gnomad4 EAS AF: 0.195

Gnomad4 SAS AF: 0.504

Gnomad4 FIN AF: 0.345

Gnomad4 NFE AF: 0.364

Gnomad4 OTH AF: 0.420

Alfa AF: 0.388 Hom.: 19875

Bravo AF: 0.446

Asia WGS AF: 0.407 AC: 1415 AN: 3478

EpiCase AF: 0.379

EpiControl AF: 0.385

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 05, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 29, 2023	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

Elliptocytosis Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Spherocytosis, Dominant Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Hereditary spherocytosis type 2 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 15, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	1.2
DANN	Benign	0.70
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8

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: rs229591; hg19: chr14-65260227; COSMIC: COSV67633734;