15-43201969-C-A

Position:

• chr15-43201969-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001114134.2(EPB42):​c.1788G>T​(p.Glu596Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: EPB42 NM_001114134.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.252

Genes affected

EPB42 (HGNC:3381): (erythrocyte membrane protein band 4.2) Erythrocyte membrane protein band 4.2 is an ATP-binding protein which may regulate the association of protein 3 with ankyrin. It probably has a role in erythrocyte shape and mechanical property regulation. Mutations in the EPB42 gene are associated with recessive spherocytic elliptocytosis and recessively transmitted hereditary hemolytic anemia. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.087346286).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
EPB42	NM_001114134.2	c.1788G>T	p.Glu596Asp	missense_variant	12/13	ENST00000441366.7	NP_001107606.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
EPB42	ENST00000441366.7	c.1788G>T	p.Glu596Asp	missense_variant	12/13	1	NM_001114134.2	ENSP00000396616	P1
EPB42	ENST00000567019.2	n.1294G>T		non_coding_transcript_exon_variant	7/8	1
EPB42	ENST00000648595.1	c.1878G>T	p.Glu626Asp	missense_variant	12/13			ENSP00000497777
EPB42	ENST00000540029.5	c.1554G>T	p.Glu518Asp	missense_variant	11/12	2		ENSP00000444699

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 17, 2023

The c.1878G>T (p.E626D) alteration is located in exon 12 (coding exon 12) of the EPB42 gene. This alteration results from a G to T substitution at nucleotide position 1878, causing the glutamic acid (E) at amino acid position 626 to be replaced by an aspartic acid (D). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.098	T
BayesDel_noAF	Benign	-0.38
CADD	Benign	19
DANN	Uncertain	0.99
DEOGEN2	Benign	0.090	.;.;.;T;.
Eigen	Benign	-0.47
Eigen_PC	Benign	-0.48
FATHMM_MKL	Benign	0.17	N
LIST_S2	Benign	0.76	.;T;T;T;T
M_CAP	Benign	0.010	T
MetaRNN	Benign	0.087	T;T;T;T;T
MetaSVM	Benign	-0.91	T
MutationAssessor	Uncertain	2.6	.;.;.;M;.
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-0.96	.;.;N;N;.
REVEL	Benign	0.018
Sift	Benign	0.40	.;.;T;T;.
Sift4G	Benign	0.46	.;.;T;T;T
Polyphen		0.11	B;B;P;B;.
Vest4		0.29, 0.30, 0.31
MutPred		0.40		.;.;.;Loss of ubiquitination at K597 (P = 0.1079);.;
MVP		0.63
ClinPred		0.62	D
GERP RS		1.7
Varity_R		0.16
gMVP		0.62

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr15-43494167;