Genetic Variant NM_001114134.2:c.1988G>T (chr15-43197390-C-A) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

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

The NM_001114134.2(EPB42):c.1988G>T(p.Arg663Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,890 control chromosomes in the GnomAD database, with no homozygous occurrence. 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

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.70

Variant links:

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]

EPB42 links:

ENSG00000285117 (HGNC:):

ENSG00000285117 links:

CCNDBP1 (HGNC:1587): (cyclin D1 binding protein 1) This gene was identified by the interaction of its gene product with Grap2, a leukocyte-specific adaptor protein important for immune cell signaling. The protein encoded by this gene was shown to interact with cyclin D. Transfection of this gene in cells was reported to reduce the phosphorylation of Rb gene product by cyclin D-dependent protein kinase, and inhibit E2F1-mediated transcription activity. This protein was also found to interact with helix-loop-helix protein E12 and is thought to be a negative regulator of liver-specific gene expression. Several alternatively spliced variants have been found for this gene. [provided by RefSeq, Apr 2009]

CCNDBP1 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EPB42	NM_001114134.2 link	c.1988G>T	p.Arg663Ile	missense_variant	Exon 13 of 13	ENST00000441366.7	NP_001107606.1	P16452-1
CCNDBP1	NM_012142.5 link	c.*2549C>A		downstream_gene_variant		ENST00000300213.9	NP_036274.3	O95273-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
EPB42	ENST00000441366.7 link	c.1988G>T	p.Arg663Ile	missense_variant	Exon 13 of 13	1	NM_001114134.2	ENSP00000396616.2	P16452-1
ENSG00000285117	ENST00000563128.5 link	n.447+4454G>T		intron_variant	Intron 3 of 3	3		ENSP00000520455.1
CCNDBP1	ENST00000300213.9 link	c.*2549C>A		downstream_gene_variant		1	NM_012142.5	ENSP00000300213.4	O95273-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461890

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727248

show subpopulations

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:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

8.99e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.18

BayesDel_addAF

Benign

0.011

BayesDel_noAF

Benign

-0.22

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Benign

0.34

.;.;.;T;.

Eigen

Benign

-0.022

Eigen_PC

Benign

-0.12

FATHMM_MKL

Benign

0.66

LIST_S2

Uncertain

0.87

.;D;D;D;D

M_CAP

Uncertain

0.096

MetaRNN

Uncertain

0.53

D;D;D;D;D

MetaSVM

Benign

-0.43

MutationAssessor

Uncertain

2.8

.;.;.;M;.

PrimateAI

Benign

0.41

PROVEAN

Pathogenic

-5.1

.;.;D;D;.

REVEL

Uncertain

0.40

Sift

Uncertain

0.0020

.;.;D;D;.

Sift4G

Uncertain

0.0060

.;.;D;D;D

Polyphen

0.96

D;D;P;D;.

Vest4

0.68, 0.67, 0.69

MutPred

0.65

.;.;.;Gain of stability (P = 0.072);.;

MVP

0.77

ClinPred

0.98

GERP RS

2.3

Varity_R

0.53

gMVP

0.64

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over