15-43201895-C-T

Variant names:

• chr15-43201895-C-T
• NM_001114134.2:c.1862G>A

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_001114134.2(EPB42):​c.1862G>A​(p.Cys621Tyr) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,866 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: EPB42 NM_001114134.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.91

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]

ENSG00000285117 (HGNC:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.966

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EPB42	NM_001114134.2	c.1862G>A	p.Cys621Tyr	missense_variant	Exon 12 of 13	ENST00000441366.7	NP_001107606.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EPB42	ENST00000441366.7	c.1862G>A	p.Cys621Tyr	missense_variant	Exon 12 of 13	1	NM_001114134.2	ENSP00000396616.2
ENSG00000285117	ENST00000563128.5	n.396G>A		non_coding_transcript_exon_variant	Exon 3 of 4	3		ENSP00000520455.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461866 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 727244

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.48
BayesDel_addAF	Pathogenic	0.23	D
BayesDel_noAF	Uncertain	0.10
CADD	Uncertain	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.61	.;.;.;D;.
Eigen	Pathogenic	0.73
Eigen_PC	Pathogenic	0.67
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Benign	0.80	.;T;T;T;T
M_CAP	Benign	0.034	D
MetaRNN	Pathogenic	0.97	D;D;D;D;D
MetaSVM	Benign	-0.64	T
MutationAssessor	Pathogenic	3.0	.;.;.;M;.
PrimateAI	Uncertain	0.58	T
PROVEAN	Pathogenic	-9.6	.;.;D;D;.
REVEL	Uncertain	0.49
Sift	Uncertain	0.0010	.;.;D;D;.
Sift4G	Uncertain	0.019	.;.;D;D;D
Polyphen		1.0	D;D;D;D;.
Vest4		0.85, 0.84, 0.84
MutPred		0.86		.;.;.;Gain of phosphorylation at C621 (P = 0.0723);.;
MVP		0.71
ClinPred		1.0	D
GERP RS		4.6
Varity_R		0.98
gMVP		0.92

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: chr15-43494093;