NM_001355436.2:c.5535C>T

Variant names:

• chr14-64772598-G-A
• rs17180252
• NM_001355436.2:c.5535C>T

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.5535C>T​(p.Leu1845Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0701 in 1,609,008 control chromosomes in the GnomAD database, including 4,415 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.056 (292 hom., cov: 33)
  • Exomes 𝑓: 0.072 (4123 hom.)
• Consequence: SPTB NM_001355436.2 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.0500
• Publications: 10 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=-0.7).
• BP6: Variant 14-64772598-G-A is Benign according to our data. Variant chr14-64772598-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 257129.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.05 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0815 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.5535C>T	p.Leu1845Leu	synonymous	Exon 26 of 36	NP_001342365.1
	SPTB	NM_001024858.4		c.5535C>T	p.Leu1845Leu	synonymous	Exon 25 of 35	NP_001020029.1
	SPTB	NM_001355437.2		c.5535C>T	p.Leu1845Leu	synonymous	Exon 26 of 32	NP_001342366.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SPTB	ENST00000644917.1	MANE Select	c.5535C>T	p.Leu1845Leu	synonymous	Exon 26 of 36	ENSP00000495909.1
	SPTB	ENST00000553938.5	TSL:1	c.1530C>T	p.Leu510Leu	synonymous	Exon 7 of 18	ENSP00000451324.1
	SPTB	ENST00000389722.7	TSL:2	c.5535C>T	p.Leu1845Leu	synonymous	Exon 25 of 35	ENSP00000374372.3

Frequencies

GnomAD3 genomes AF: 0.0565 AC: 8602 AN: 152168 Hom.: 292 Cov.: 33

Gnomad AFR AF: 0.0172

Gnomad AMI AF: 0.0515

Gnomad AMR AF: 0.0529

Gnomad ASJ AF: 0.0550

Gnomad EAS AF: 0.0194

Gnomad SAS AF: 0.0290

Gnomad FIN AF: 0.0785

Gnomad MID AF: 0.0443

Gnomad NFE AF: 0.0833

Gnomad OTH AF: 0.0435

GnomAD2 exomes AF: 0.0595 AC: 14583 AN: 245264 AF XY: 0.0599

Gnomad AFR exome AF: 0.0149

Gnomad AMR exome AF: 0.0410

Gnomad ASJ exome AF: 0.0508

Gnomad EAS exome AF: 0.0264

Gnomad FIN exome AF: 0.0763

Gnomad NFE exome AF: 0.0828

Gnomad OTH exome AF: 0.0596

GnomAD4 exome AF: 0.0715 AC: 104186 AN: 1456722 Hom.: 4123 Cov.: 33 AF XY: 0.0708 AC XY: 51303 AN XY: 725100

African (AFR) AF: 0.0138 AC: 463 AN: 33472

American (AMR) AF: 0.0438 AC: 1956 AN: 44708

Ashkenazi Jewish (ASJ) AF: 0.0518 AC: 1354 AN: 26120

East Asian (EAS) AF: 0.0168 AC: 665 AN: 39694

South Asian (SAS) AF: 0.0308 AC: 2655 AN: 86238

European-Finnish (FIN) AF: 0.0783 AC: 3813 AN: 48714

Middle Eastern (MID) AF: 0.0381 AC: 214 AN: 5610

European-Non Finnish (NFE) AF: 0.0802 AC: 89135 AN: 1111860

Other (OTH) AF: 0.0652 AC: 3931 AN: 60306

GnomAD4 genome AF: 0.0565 AC: 8603 AN: 152286 Hom.: 292 Cov.: 33 AF XY: 0.0565 AC XY: 4208 AN XY: 74468

African (AFR) AF: 0.0172 AC: 715 AN: 41576

American (AMR) AF: 0.0529 AC: 809 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.0550 AC: 191 AN: 3472

East Asian (EAS) AF: 0.0195 AC: 101 AN: 5182

South Asian (SAS) AF: 0.0288 AC: 139 AN: 4826

European-Finnish (FIN) AF: 0.0785 AC: 833 AN: 10608

Middle Eastern (MID) AF: 0.0442 AC: 13 AN: 294

European-Non Finnish (NFE) AF: 0.0833 AC: 5662 AN: 67998

Other (OTH) AF: 0.0440 AC: 93 AN: 2114

Alfa AF: 0.0725 Hom.: 259

Bravo AF: 0.0522

Asia WGS AF: 0.0560 AC: 194 AN: 3478

EpiCase AF: 0.0749

EpiControl AF: 0.0748

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Jan 27, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Nov 25, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

not specified Benign:1

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Elliptocytosis Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Spherocytosis, Dominant Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.70
CADD	Benign	12
DANN	Benign	0.93
PhyloP100		0.050
Mutation Taster		=99/1	polymorphism (auto)

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

Other links and lift over

dbSNP: rs17180252; hg19: chr14-65239316;