chr14-64753621-C-G

Position:

chr14-64753621-C-G

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4_StrongBP6

The NM_001355436.2(SPTB):c.6518G>C(p.Arg2173Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000113 in 1,613,660 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00064 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000059 ( 1 hom. )

Consequence

SPTB
NM_001355436.2 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:2

Conservation

PhyloP100: 0.0690

Variant links:

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]

SPTB links:

SPTB (HGNC:):

SPTB links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -5 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.009253025).

BP6

Variant 14-64753621-C-G is Benign according to our data. Variant chr14-64753621-C-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 2560857.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SPTB	NM_001355436.2 linkuse as main transcript	c.6518G>C	p.Arg2173Pro	missense_variant	33/36	ENST00000644917.1	NP_001342365.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SPTB	ENST00000644917.1 linkuse as main transcript	c.6518G>C	p.Arg2173Pro	missense_variant	33/36		NM_001355436.2	ENSP00000495909.1		P11277-2

Frequencies

GnomAD3 genomes

AF:

0.000618

AC:

AN:

152134

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00222

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000163

AC:

AN:

251054

Hom.:

AF XY:

0.000118

AC XY:

AN XY:

135822

show subpopulations

Gnomad AFR exome

AF:

0.00191

Gnomad AMR exome

AF:

0.000202

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000980

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000588

AC:

AN:

1461408

Hom.:

Cov.:

AF XY:

0.0000523

AC XY:

AN XY:

726996

show subpopulations

Gnomad4 AFR exome

AF:

0.00185

Gnomad4 AMR exome

AF:

0.000157

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000696

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.000182

GnomAD4 genome

AF:

0.000637

AC:

AN:

152252

Hom.:

Cov.:

AF XY:

0.000739

AC XY:

AN XY:

74460

show subpopulations

Gnomad4 AFR

AF:

0.00229

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.000706

ESP6500AA

AF:

0.00295

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000247

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 10, 2023

The c.6518G>C (p.R2173P) alteration is located in exon 32 (coding exon 32) of the SPTB gene. This alteration results from a G to C substitution at nucleotide position 6518, causing the arginine (R) at amino acid position 2173 to be replaced by a proline (P). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

SPTB-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 03, 2022

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

not provided

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Dec 01, 2022

SPTB: BP4 -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.48

BayesDel_noAF

Benign

-0.47

CADD

Benign

DANN

Benign

0.94

DEOGEN2

Benign

0.0022

.;.;.;T

Eigen

Benign

-0.83

Eigen_PC

Benign

-0.75

FATHMM_MKL

Benign

0.039

LIST_S2

Benign

0.42

.;.;T;T

M_CAP

Benign

0.018

MetaRNN

Benign

0.0093

T;T;T;T

MetaSVM

Benign

-1.1

PrimateAI

Benign

0.42

PROVEAN

Benign

-0.37

N;.;N;N

REVEL

Benign

0.041

Sift

Benign

0.34

T;.;T;T

Sift4G

Benign

0.45

T;.;T;T

Vest4

0.47

MVP

0.16

MPC

0.28

ClinPred

0.012

GERP RS

1.1

gMVP

0.23

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over