rs121918646

chr14-64801797-A-G

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2 PP3_Strong PP5

The NM_001355436.2(SPTB):c.604T>C(p.Trp202Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: SPTB NM_001355436.2 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 9.29

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.991
• PP5: Variant 14-64801797-A-G is Pathogenic according to our data. Variant chr14-64801797-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 12835.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SPTB	NM_001355436.2	c.604T>C	p.Trp202Arg	missense_variant	6/36	ENST00000644917.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SPTB	ENST00000644917.1	c.604T>C	p.Trp202Arg	missense_variant	6/36		NM_001355436.2	P1
SPTB	ENST00000389722.7	c.604T>C	p.Trp202Arg	missense_variant	5/35	2		P1
SPTB	ENST00000389720.4	c.604T>C	p.Trp202Arg	missense_variant	6/32	5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Hereditary spherocytosis type 2 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Aug 01, 1993

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.39	D
BayesDel_noAF	Pathogenic	0.33
Cadd	Pathogenic	32
Dann	Uncertain	1.0
Eigen	Pathogenic	0.96
Eigen_PC	Pathogenic	0.81
FATHMM_MKL	Pathogenic	0.97	D
M_CAP	Uncertain	0.20	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D
MetaSVM	Uncertain	0.62	D
MutationAssessor	Pathogenic	4.0	H;H;H;H;H
MutationTaster	Benign	1.0	A;A;A;A;A
PrimateAI	Pathogenic	0.90	D
PROVEAN	Pathogenic	-13	D;.;D;D;D
REVEL	Pathogenic	0.65
Sift	Pathogenic	0.0	D;.;D;D;D
Sift4G	Pathogenic	0.0010	D;.;D;D;D
Polyphen		1.0	.;.;.;D;D
Vest4		1.0
MutPred		0.98		Gain of disorder (P = 0.0174);Gain of disorder (P = 0.0174);Gain of disorder (P = 0.0174);Gain of disorder (P = 0.0174);Gain of disorder (P = 0.0174);
MVP		0.95
MPC		2.2
ClinPred		1.0	D
GERP RS		4.3
Varity_R		0.97
gMVP		0.98

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs121918646; hg19: chr14-65268515;