rs1626923

Variant names:

• chr14-64779905-T-C
• rs1626923
• NM_001355436.2:c.4293A>G

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001355436.2(SPTB):​c.4293A>G​(p.Arg1431Arg) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.337 in 1,613,268 control chromosomes in the GnomAD database, including 96,736 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.40 (13942 hom., cov: 31)
  • Exomes 𝑓: 0.33 (82794 hom.)
• Consequence: SPTB NM_001355436.2 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -1.31
• Publications: 19 publications found

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 Gene-Disease associations (from GenCC):

• hereditary spherocytosis type 2

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• elliptocytosis 3

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• hereditary elliptocytosis

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• hereditary spherocytosis

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.55).
• BP6: Variant 14-64779905-T-C is Benign according to our data. Variant chr14-64779905-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 257117.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.31 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.623 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001355436.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SPTB	NM_001355436.2	MANE Select	c.4293A>G	p.Arg1431Arg	synonymous	Exon 21 of 36	NP_001342365.1
	SPTB	NM_001024858.4		c.4293A>G	p.Arg1431Arg	synonymous	Exon 20 of 35	NP_001020029.1
	SPTB	NM_001355437.2		c.4293A>G	p.Arg1431Arg	synonymous	Exon 21 of 32	NP_001342366.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SPTB	ENST00000644917.1	MANE Select	c.4293A>G	p.Arg1431Arg	synonymous	Exon 21 of 36	ENSP00000495909.1
	SPTB	ENST00000553938.5	TSL:1	c.288A>G	p.Arg96Arg	synonymous	Exon 2 of 18	ENSP00000451324.1
	SPTB	ENST00000389722.7	TSL:2	c.4293A>G	p.Arg1431Arg	synonymous	Exon 20 of 35	ENSP00000374372.3

Frequencies

GnomAD3 genomes AF: 0.402 AC: 61031 AN: 151840 Hom.: 13911 Cov.: 31

Gnomad AFR AF: 0.629

Gnomad AMI AF: 0.297

Gnomad AMR AF: 0.267

Gnomad ASJ AF: 0.330

Gnomad EAS AF: 0.364

Gnomad SAS AF: 0.412

Gnomad FIN AF: 0.302

Gnomad MID AF: 0.358

Gnomad NFE AF: 0.318

Gnomad OTH AF: 0.373

GnomAD2 exomes AF: 0.336 AC: 84212 AN: 250516 AF XY: 0.339

Gnomad AFR exome AF: 0.638

Gnomad AMR exome AF: 0.190

Gnomad ASJ exome AF: 0.327

Gnomad EAS exome AF: 0.364

Gnomad FIN exome AF: 0.299

Gnomad NFE exome AF: 0.322

Gnomad OTH exome AF: 0.328

GnomAD4 exome AF: 0.330 AC: 482373 AN: 1461310 Hom.: 82794 Cov.: 45 AF XY: 0.332 AC XY: 241371 AN XY: 726948

African (AFR) AF: 0.645 AC: 21586 AN: 33474

American (AMR) AF: 0.200 AC: 8958 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.332 AC: 8686 AN: 26136

East Asian (EAS) AF: 0.353 AC: 14011 AN: 39698

South Asian (SAS) AF: 0.399 AC: 34455 AN: 86254

European-Finnish (FIN) AF: 0.296 AC: 15792 AN: 53320

Middle Eastern (MID) AF: 0.342 AC: 1970 AN: 5768

European-Non Finnish (NFE) AF: 0.320 AC: 355570 AN: 1111572

Other (OTH) AF: 0.354 AC: 21345 AN: 60364

GnomAD4 genome AF: 0.402 AC: 61106 AN: 151958 Hom.: 13942 Cov.: 31 AF XY: 0.400 AC XY: 29677 AN XY: 74252

African (AFR) AF: 0.630 AC: 26082 AN: 41428

American (AMR) AF: 0.267 AC: 4078 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.330 AC: 1143 AN: 3468

East Asian (EAS) AF: 0.363 AC: 1871 AN: 5160

South Asian (SAS) AF: 0.412 AC: 1981 AN: 4814

European-Finnish (FIN) AF: 0.302 AC: 3183 AN: 10552

Middle Eastern (MID) AF: 0.371 AC: 109 AN: 294

European-Non Finnish (NFE) AF: 0.318 AC: 21599 AN: 67952

Other (OTH) AF: 0.374 AC: 790 AN: 2110

Alfa AF: 0.344 Hom.: 21408

Bravo AF: 0.406

Asia WGS AF: 0.418 AC: 1456 AN: 3478

EpiCase AF: 0.323

EpiControl AF: 0.326

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	1	Elliptocytosis (1)
-	-	1	Hereditary spherocytosis type 2 (1)
-	-	1	not specified (1)
-	-	1	Spherocytosis, Dominant (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.55
CADD	Benign	8.4
DANN	Benign	0.71
PhyloP100		-1.3
Mutation Taster		=97/3	polymorphism (auto)

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

Other links and lift over

dbSNP: rs1626923; hg19: chr14-65246623; COSMIC: COSV67633848;