NM_001355436.2:c.1269G>A

Variant names:

• chr14-64796629-C-T
• rs229586
• NM_001355436.2:c.1269G>A

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_001355436.2(SPTB):​c.1269G>A​(p.Leu423Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.254 in 1,614,024 control chromosomes in the GnomAD database, including 53,837 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.26 (5071 hom., cov: 32)
  • Exomes 𝑓: 0.25 (48766 hom.)
• Consequence: SPTB NM_001355436.2 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 0.265
• Publications: 21 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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.39).
• BP6: Variant 14-64796629-C-T is Benign according to our data. Variant chr14-64796629-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 257097.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.265 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.37 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.1269G>A	p.Leu423Leu	synonymous	Exon 11 of 36	NP_001342365.1
	SPTB	NM_001024858.4		c.1269G>A	p.Leu423Leu	synonymous	Exon 10 of 35	NP_001020029.1
	SPTB	NM_001355437.2		c.1269G>A	p.Leu423Leu	synonymous	Exon 11 of 32	NP_001342366.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SPTB	ENST00000644917.1	MANE Select	c.1269G>A	p.Leu423Leu	synonymous	Exon 11 of 36	ENSP00000495909.1
	SPTB	ENST00000389722.7	TSL:2	c.1269G>A	p.Leu423Leu	synonymous	Exon 10 of 35	ENSP00000374372.3
	SPTB	ENST00000961380.1		c.1269G>A	p.Leu423Leu	synonymous	Exon 12 of 37	ENSP00000631439.1

Frequencies

GnomAD3 genomes AF: 0.256 AC: 38868 AN: 152066 Hom.: 5067 Cov.: 32

Gnomad AFR AF: 0.268

Gnomad AMI AF: 0.273

Gnomad AMR AF: 0.213

Gnomad ASJ AF: 0.259

Gnomad EAS AF: 0.292

Gnomad SAS AF: 0.385

Gnomad FIN AF: 0.226

Gnomad MID AF: 0.326

Gnomad NFE AF: 0.250

Gnomad OTH AF: 0.261

GnomAD2 exomes AF: 0.259 AC: 65031 AN: 251418 AF XY: 0.266

Gnomad AFR exome AF: 0.270

Gnomad AMR exome AF: 0.185

Gnomad ASJ exome AF: 0.255

Gnomad EAS exome AF: 0.263

Gnomad FIN exome AF: 0.222

Gnomad NFE exome AF: 0.255

Gnomad OTH exome AF: 0.260

GnomAD4 exome AF: 0.254 AC: 371754 AN: 1461838 Hom.: 48766 Cov.: 42 AF XY: 0.259 AC XY: 188322 AN XY: 727228

African (AFR) AF: 0.270 AC: 9047 AN: 33478

American (AMR) AF: 0.193 AC: 8642 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.265 AC: 6921 AN: 26136

East Asian (EAS) AF: 0.281 AC: 11147 AN: 39698

South Asian (SAS) AF: 0.372 AC: 32111 AN: 86258

European-Finnish (FIN) AF: 0.223 AC: 11899 AN: 53406

Middle Eastern (MID) AF: 0.267 AC: 1542 AN: 5768

European-Non Finnish (NFE) AF: 0.247 AC: 274785 AN: 1111976

Other (OTH) AF: 0.259 AC: 15660 AN: 60394

GnomAD4 genome AF: 0.256 AC: 38888 AN: 152186 Hom.: 5071 Cov.: 32 AF XY: 0.256 AC XY: 19065 AN XY: 74410

African (AFR) AF: 0.268 AC: 11126 AN: 41502

American (AMR) AF: 0.213 AC: 3255 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.259 AC: 900 AN: 3470

East Asian (EAS) AF: 0.291 AC: 1502 AN: 5160

South Asian (SAS) AF: 0.384 AC: 1855 AN: 4830

European-Finnish (FIN) AF: 0.226 AC: 2390 AN: 10598

Middle Eastern (MID) AF: 0.337 AC: 99 AN: 294

European-Non Finnish (NFE) AF: 0.249 AC: 16968 AN: 68010

Other (OTH) AF: 0.257 AC: 544 AN: 2114

Alfa AF: 0.251 Hom.: 10666

Bravo AF: 0.253

Asia WGS AF: 0.342 AC: 1187 AN: 3478

EpiCase AF: 0.256

EpiControl AF: 0.256

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	-0.39
CADD	Benign	9.0
DANN	Benign	0.76
PhyloP100		0.27
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Mutation Taster		=94/6	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: rs229586; hg19: chr14-65263347; COSMIC: COSV67630508;