rs229592

Variant names:

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

Your query was ambiguous. Multiple possible variants found:

• chr14-64774510-A-C
• chr14-64774510-A-G
• chr14-64774510-A-T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001355436.2(SPTB):​c.4860T>G​(p.Ile1620Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000713 in 1,401,706 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. I1620I) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.1e-7 (0 hom.)
• Consequence: SPTB NM_001355436.2 missense
• Clinical Significance: Not reported in ClinVar
• 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: 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.10016614).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SPTB	NM_001355436.2	c.4860T>G	p.Ile1620Met	missense_variant	Exon 24 of 36	ENST00000644917.1	NP_001342365.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SPTB	ENST00000644917.1	c.4860T>G	p.Ile1620Met	missense_variant	Exon 24 of 36		NM_001355436.2	ENSP00000495909.1
SPTB	ENST00000553938.5	c.855T>G	p.Ile285Met	missense_variant	Exon 5 of 18	1		ENSP00000451324.1
SPTB	ENST00000389722.7	c.4860T>G	p.Ile1620Met	missense_variant	Exon 23 of 35	2		ENSP00000374372.3
SPTB	ENST00000389720.4	c.4860T>G	p.Ile1620Met	missense_variant	Exon 24 of 32	5		ENSP00000374370.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.13e-7 AC: 1 AN: 1401706 Hom.: 0 Cov.: 35 AF XY: 0.00 AC XY: 0 AN XY: 691678

African (AFR) AF: 0.00 AC: 0 AN: 31754

American (AMR) AF: 0.00 AC: 0 AN: 36098

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25192

East Asian (EAS) AF: 0.00 AC: 0 AN: 36006

South Asian (SAS) AF: 0.00 AC: 0 AN: 79406

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49052

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5696

European-Non Finnish (NFE) AF: 9.26e-7 AC: 1 AN: 1080378

Other (OTH) AF: 0.00 AC: 0 AN: 58124

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.075
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.59
CADD	Benign	7.9
DANN	Benign	0.92
DEOGEN2	Benign	0.0080	.;.;.;T;T;T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.068	N
LIST_S2	Uncertain	0.89	.;.;D;T;.;D
M_CAP	Benign	0.014	T
MetaRNN	Benign	0.10	T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.0	L;L;L;.;L;L
PhyloP100		-1.2
PrimateAI	Benign	0.42	T
PROVEAN	Benign	0.33	N;.;N;N;N;N
REVEL	Benign	0.078
Sift	Benign	0.12	T;.;T;T;T;T
Sift4G	Benign	0.18	T;.;T;T;T;T
Polyphen		0.016	.;.;.;.;B;B
Vest4		0.11
MutPred		0.47		Gain of disorder (P = 0.0555);Gain of disorder (P = 0.0555);Gain of disorder (P = 0.0555);.;Gain of disorder (P = 0.0555);Gain of disorder (P = 0.0555);
MVP		0.20
MPC		0.21
ClinPred		0.50	T
GERP RS		-3.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.23
gMVP		0.078
Mutation Taster		=72/28	polymorphism

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;