NM_001355436.2:c.4222G>C

Variant names:

• chr14-64782334-C-G
• rs17245552
• NM_001355436.2:c.4222G>C

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 1P and 20B. PP3 BP4_Strong BP6_Very_Strong BA1

The NM_001355436.2(SPTB):​c.4222G>C​(p.Gly1408Arg) variant causes a missense change. The variant allele was found at a frequency of 0.0625 in 1,614,122 control chromosomes in the GnomAD database, including 3,983 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. G1408G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.063 (435 hom., cov: 32)
  • Exomes 𝑓: 0.062 (3548 hom.)
• Consequence: SPTB NM_001355436.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 6.15
• 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: 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 -19 ACMG points.

• PP3: Multiple lines of computational evidence support a deleterious effect 6: Cadd, Dann, Eigen, FATHMM_MKL, MutationAssessor, PROVEAN [when BayesDel_addAF, max_spliceai, MetaRNN, MutationTaster was below the threshold]
• BP4: Computational evidence support a benign effect (MetaRNN=0.0017653108).
• BP6: Variant 14-64782334-C-G is Benign according to our data. Variant chr14-64782334-C-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 257115.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.204 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.4222G>C	p.Gly1408Arg	missense	Exon 20 of 36	NP_001342365.1	P11277-2
	SPTB	NM_001024858.4		c.4222G>C	p.Gly1408Arg	missense	Exon 19 of 35	NP_001020029.1	P11277-2
	SPTB	NM_001355437.2		c.4222G>C	p.Gly1408Arg	missense	Exon 20 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.4222G>C	p.Gly1408Arg	missense	Exon 20 of 36	ENSP00000495909.1	P11277-2
	SPTB	ENST00000553938.5	TSL:1	c.217G>C	p.Gly73Arg	missense	Exon 1 of 18	ENSP00000451324.1	H0YJE6
	SPTB	ENST00000389722.7	TSL:2	c.4222G>C	p.Gly1408Arg	missense	Exon 19 of 35	ENSP00000374372.3	P11277-2

Frequencies

GnomAD3 genomes AF: 0.0629 AC: 9567 AN: 152140 Hom.: 439 Cov.: 32

Gnomad AFR AF: 0.0774

Gnomad AMI AF: 0.0241

Gnomad AMR AF: 0.0292

Gnomad ASJ AF: 0.0418

Gnomad EAS AF: 0.216

Gnomad SAS AF: 0.0961

Gnomad FIN AF: 0.0365

Gnomad MID AF: 0.0411

Gnomad NFE AF: 0.0537

Gnomad OTH AF: 0.0526

GnomAD2 exomes AF: 0.0654 AC: 16449 AN: 251426 AF XY: 0.0668

Gnomad AFR exome AF: 0.0780

Gnomad AMR exome AF: 0.0223

Gnomad ASJ exome AF: 0.0416

Gnomad EAS exome AF: 0.213

Gnomad FIN exome AF: 0.0353

Gnomad NFE exome AF: 0.0532

Gnomad OTH exome AF: 0.0529

GnomAD4 exome AF: 0.0625 AC: 91323 AN: 1461866 Hom.: 3548 Cov.: 32 AF XY: 0.0633 AC XY: 46052 AN XY: 727232

African (AFR) AF: 0.0816 AC: 2731 AN: 33480

American (AMR) AF: 0.0237 AC: 1060 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0399 AC: 1044 AN: 26136

East Asian (EAS) AF: 0.200 AC: 7936 AN: 39698

South Asian (SAS) AF: 0.0935 AC: 8064 AN: 86258

European-Finnish (FIN) AF: 0.0359 AC: 1918 AN: 53398

Middle Eastern (MID) AF: 0.0397 AC: 229 AN: 5768

European-Non Finnish (NFE) AF: 0.0579 AC: 64361 AN: 1112008

Other (OTH) AF: 0.0659 AC: 3980 AN: 60396

GnomAD4 genome AF: 0.0628 AC: 9569 AN: 152256 Hom.: 435 Cov.: 32 AF XY: 0.0636 AC XY: 4738 AN XY: 74456

African (AFR) AF: 0.0774 AC: 3216 AN: 41536

American (AMR) AF: 0.0291 AC: 446 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.0418 AC: 145 AN: 3472

East Asian (EAS) AF: 0.215 AC: 1110 AN: 5172

South Asian (SAS) AF: 0.0959 AC: 463 AN: 4826

European-Finnish (FIN) AF: 0.0365 AC: 387 AN: 10608

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

European-Non Finnish (NFE) AF: 0.0538 AC: 3657 AN: 68018

Other (OTH) AF: 0.0520 AC: 110 AN: 2114

Alfa AF: 0.0550 Hom.: 85

Bravo AF: 0.0623

TwinsUK AF: 0.0577 AC: 214

ALSPAC AF: 0.0649 AC: 250

ESP6500AA AF: 0.0717 AC: 316

ESP6500EA AF: 0.0569 AC: 489

ExAC AF: 0.0675 AC: 8191

Asia WGS AF: 0.121 AC: 422 AN: 3478

EpiCase AF: 0.0489

EpiControl AF: 0.0479

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	not specified (1)
-	-	1	Spherocytosis, Dominant (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.49
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Uncertain	-0.030
CADD	Pathogenic	27
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.34	T
Eigen	Pathogenic	0.82
Eigen_PC	Pathogenic	0.78
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.87	D
MetaRNN	Benign	0.0018	T
MetaSVM	Benign	-1.2	T
MutationAssessor	Pathogenic	3.0	M
PhyloP100		6.1
PrimateAI	Uncertain	0.63	T
PROVEAN	Pathogenic	-5.6	D
REVEL	Uncertain	0.41
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0030	D
Polyphen		1.0	D
Vest4		0.18
MPC		0.83
ClinPred		0.015	T
GERP RS		5.4
PromoterAI		0.024	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.2
Varity_R		0.73
gMVP		0.66
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: rs17245552; hg19: chr14-65249052; COSMIC: COSV67631852; COSMIC: COSV67631852;