rs229592

Variant names:

• chr14-64774510-A-G
• rs229592
• NM_001355436.2:c.4860T>C

Your query was ambiguous. Multiple possible variants found:

• chr14-64774510-A-G
• chr14-64774510-A-C
• chr14-64774510-A-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.4860T>C​(p.Ile1620Ile) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.284 in 1,553,578 control chromosomes in the GnomAD database, including 73,904 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.41 (16309 hom., cov: 32)
  • Exomes 𝑓: 0.27 (57595 hom.)
• Consequence: SPTB NM_001355436.2 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -1.24
• Publications: 20 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: PanelApp Australia, Labcorp Genetics (formerly Invitae)
• elliptocytosis 3

  Inheritance: AR, AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), PanelApp Australia
• 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=-0.76).
• BP6: Variant 14-64774510-A-G is Benign according to our data. Variant chr14-64774510-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 257128.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.24 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.745 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SPTB	NM_001355436.2	MANE Select	c.4860T>C	p.Ile1620Ile	synonymous	Exon 24 of 36	NP_001342365.1	P11277-2
	SPTB	NM_001024858.4		c.4860T>C	p.Ile1620Ile	synonymous	Exon 23 of 35	NP_001020029.1	P11277-2
	SPTB	NM_001355437.2		c.4860T>C	p.Ile1620Ile	synonymous	Exon 24 of 32	NP_001342366.1	P11277-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SPTB	ENST00000644917.1	MANE Select	c.4860T>C	p.Ile1620Ile	synonymous	Exon 24 of 36	ENSP00000495909.1	P11277-2
	SPTB	ENST00000553938.5	TSL:1	c.855T>C	p.Ile285Ile	synonymous	Exon 5 of 18	ENSP00000451324.1	H0YJE6
	SPTB	ENST00000389722.7	TSL:2	c.4860T>C	p.Ile1620Ile	synonymous	Exon 23 of 35	ENSP00000374372.3	P11277-2

Frequencies

GnomAD3 genomes AF: 0.410 AC: 62253 AN: 151850 Hom.: 16267 Cov.: 32

Gnomad AFR AF: 0.751

Gnomad AMI AF: 0.243

Gnomad AMR AF: 0.328

Gnomad ASJ AF: 0.278

Gnomad EAS AF: 0.464

Gnomad SAS AF: 0.316

Gnomad FIN AF: 0.342

Gnomad MID AF: 0.345

Gnomad NFE AF: 0.244

Gnomad OTH AF: 0.374

GnomAD2 exomes AF: 0.324 AC: 51720 AN: 159502 AF XY: 0.315

Gnomad AFR exome AF: 0.764

Gnomad AMR exome AF: 0.325

Gnomad ASJ exome AF: 0.284

Gnomad EAS exome AF: 0.467

Gnomad FIN exome AF: 0.341

Gnomad NFE exome AF: 0.245

Gnomad OTH exome AF: 0.319

GnomAD4 exome AF: 0.270 AC: 378130 AN: 1401610 Hom.: 57595 Cov.: 35 AF XY: 0.269 AC XY: 186176 AN XY: 691638

African (AFR) AF: 0.776 AC: 24633 AN: 31752

American (AMR) AF: 0.328 AC: 11831 AN: 36094

Ashkenazi Jewish (ASJ) AF: 0.283 AC: 7131 AN: 25190

East Asian (EAS) AF: 0.489 AC: 17609 AN: 35998

South Asian (SAS) AF: 0.298 AC: 23645 AN: 79406

European-Finnish (FIN) AF: 0.335 AC: 16408 AN: 49008

Middle Eastern (MID) AF: 0.308 AC: 1754 AN: 5694

European-Non Finnish (NFE) AF: 0.238 AC: 257171 AN: 1080350

Other (OTH) AF: 0.309 AC: 17948 AN: 58118

GnomAD4 genome AF: 0.410 AC: 62356 AN: 151968 Hom.: 16309 Cov.: 32 AF XY: 0.412 AC XY: 30624 AN XY: 74286

African (AFR) AF: 0.752 AC: 31163 AN: 41460

American (AMR) AF: 0.328 AC: 5017 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.278 AC: 966 AN: 3472

East Asian (EAS) AF: 0.466 AC: 2387 AN: 5126

South Asian (SAS) AF: 0.314 AC: 1512 AN: 4820

European-Finnish (FIN) AF: 0.342 AC: 3615 AN: 10564

Middle Eastern (MID) AF: 0.357 AC: 105 AN: 294

European-Non Finnish (NFE) AF: 0.244 AC: 16576 AN: 67926

Other (OTH) AF: 0.376 AC: 794 AN: 2112

Alfa AF: 0.305 Hom.: 29624

Bravo AF: 0.430

Asia WGS AF: 0.414 AC: 1440 AN: 3478

ClinVar

ClinVar submissions

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	-0.76
CADD	Benign	1.9
DANN	Benign	0.60
PhyloP100		-1.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=96/4	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: rs229592; hg19: chr14-65241228; COSMIC: COSV67630256;