6-130869636-T-A

Variant summary

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

The NM_001431.4(EPB41L2):c.2534A>T(p.Glu845Val) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: EPB41L2 NM_001431.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.17

Genes affected

EPB41L2 (HGNC:3379): (erythrocyte membrane protein band 4.1 like 2) Predicted to enable PH domain binding activity; cytoskeletal protein binding activity; and structural molecule activity. Involved in positive regulation of protein localization to cell cortex. Located in cell junction; nucleoplasm; and plasma membrane. Colocalizes with COP9 signalosome. [provided by Alliance of Genome Resources, Apr 2022]

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=0.24136212).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EPB41L2	NM_001431.4	c.2534A>T	p.Glu845Val	missense_variant	15/20	ENST00000337057.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EPB41L2	ENST00000337057.8	c.2534A>T	p.Glu845Val	missense_variant	15/20	1	NM_001431.4	P2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 10, 2022

The c.2534A>T (p.E845V) alteration is located in exon 15 (coding exon 14) of the EPB41L2 gene. This alteration results from a A to T substitution at nucleotide position 2534, causing the glutamic acid (E) at amino acid position 845 to be replaced by a valine (V). 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	0.092
BayesDel_addAF	Uncertain	0.045	T
BayesDel_noAF	Benign	-0.17
Cadd	Uncertain	23
Dann	Uncertain	0.99
DEOGEN2	Benign	0.12	T;.;T;.;.;.;T
Eigen	Uncertain	0.52
Eigen_PC	Uncertain	0.56
FATHMM_MKL	Pathogenic	0.98	D
M_CAP	Benign	0.041	D
MetaRNN	Benign	0.24	T;T;T;T;T;T;T
MetaSVM	Benign	-1.2	T
MutationAssessor	Uncertain	2.1	M;.;M;.;.;.;.
MutationTaster	Benign	0.98	D;D;D;D;D;D;D;D;D;D;D;D;D;D
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-1.6	N;.;N;D;N;D;D
REVEL	Benign	0.16
Sift	Uncertain	0.0040	D;.;D;D;D;D;D
Sift4G	Benign	0.082	T;T;T;T;D;T;D
Polyphen		0.84	P;.;P;.;D;.;.
Vest4		0.48
MutPred		0.26		Gain of methylation at K848 (P = 0.1013);.;Gain of methylation at K848 (P = 0.1013);.;.;.;.;
MVP		0.42
MPC		0.18
ClinPred		0.80	D
GERP RS		5.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.15
gMVP		0.52

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: chr6-131190776;