6-130865598-G-C

Variant summary

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

The NM_001431.4(EPB41L2):c.2767C>G(p.Leu923Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,212 control chromosomes in the GnomAD database, with no homozygous occurrence. 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: 𝑓 0.0000066 (0 hom., cov: 33)
• Consequence: EPB41L2 NM_001431.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.40

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=0.21743238).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EPB41L2	NM_001431.4	c.2767C>G	p.Leu923Val	missense_variant	17/20	ENST00000337057.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EPB41L2	ENST00000337057.8	c.2767C>G	p.Leu923Val	missense_variant	17/20	1	NM_001431.4	P2

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152212 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 30

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152212 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 74366

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000756

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

Aug 28, 2023

The c.2767C>G (p.L923V) alteration is located in exon 17 (coding exon 16) of the EPB41L2 gene. This alteration results from a C to G substitution at nucleotide position 2767, causing the leucine (L) at amino acid position 923 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	0.087
BayesDel_addAF	Benign	-0.032	T
BayesDel_noAF	Benign	-0.28
Cadd	Benign	20
Dann	Uncertain	0.99
Eigen	Benign	-0.25
Eigen_PC	Benign	-0.11
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.86	D;.;D;D;.;D;D;.;D;D;D;.;D
M_CAP	Benign	0.045	D
MetaRNN	Benign	0.22	T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.86	T
MutationTaster	Benign	0.93	D;D;D;D;D;N;N;N;N;N;N;N;N;N
PrimateAI	Uncertain	0.51	T
PROVEAN	Benign	-1.8	N;N;N;N;N;.;N;N;N;N;N;N;N
REVEL	Benign	0.18
Sift	Benign	0.67	T;T;T;T;T;.;T;T;T;T;T;T;T
Sift4G	Benign	0.18	T;T;T;T;D;T;D;T;D;T;T;T;.
Polyphen		0.017, 0.0050	.;.;.;.;B;.;B;.;B;.;.;.;.
Vest4		0.33
MutPred		0.52		.;.;.;.;Gain of sheet (P = 0.0125);.;Gain of sheet (P = 0.0125);.;.;.;.;.;.;
MVP		0.43
MPC		0.54
ClinPred		0.91	D
GERP RS		2.9
Varity_R		0.096
gMVP		0.15

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs753806085; hg19: chr6-131186738;