Genetic Variant EPB41L2:p.Cys866Tyr (chr6-130869573-C-T) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001431.4(EPB41L2):c.2597G>A(p.Cys866Tyr) variant causes a missense change. The variant allele was found at a frequency of 0.00000205 in 1,461,598 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. C866F) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

EPB41L2
NM_001431.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 7.16

Publications

0 publications found

Variant links:

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]

EPB41L2 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001431.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
EPB41L2	NM_001431.4	MANE Select	c.2597G>A	p.Cys866Tyr	missense	Exon 15 of 20	NP_001422.1	O43491-1
EPB41L2	NM_001350299.2		c.2753G>A	p.Cys918Tyr	missense	Exon 17 of 22	NP_001337228.1	A0A994J5B1
EPB41L2	NM_001350301.2		c.2753G>A	p.Cys918Tyr	missense	Exon 17 of 21	NP_001337230.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
EPB41L2	ENST00000337057.8	TSL:1 MANE Select	c.2597G>A	p.Cys866Tyr	missense	Exon 15 of 20	ENSP00000338481.3	O43491-1
EPB41L2	ENST00000524581.5	TSL:1	c.731G>A	p.Cys244Tyr	missense	Exon 4 of 9	ENSP00000437207.1	Q6R5J7
EPB41L2	ENST00000528282.5	TSL:1	c.1834-1992G>A		intron	N/A	ENSP00000434308.1	O43491-3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000205

AC:

AN:

1461598

Hom.:

Cov.:

AF XY:

0.00000413

AC XY:

AN XY:

727096

show subpopulations

African (AFR)

AF:

0.0000597

AC:

AN:

33478

American (AMR)

AF:

0.00

AC:

AN:

44708

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26104

East Asian (EAS)

AF:

0.00

AC:

AN:

39698

South Asian (SAS)

AF:

0.00

AC:

AN:

86214

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53400

Middle Eastern (MID)

AF:

0.000173

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1111842

Other (OTH)

AF:

0.00

AC:

AN:

60388

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.492

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.42

BayesDel_addAF

Pathogenic

0.25

BayesDel_noAF

Uncertain

0.12

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.23

Eigen

Pathogenic

0.79

Eigen_PC

Pathogenic

0.79

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.95

M_CAP

Benign

0.028

MetaRNN

Uncertain

0.60

MetaSVM

Benign

-0.96

MutationAssessor

Uncertain

2.2

PhyloP100

7.2

PrimateAI

Uncertain

0.78

PROVEAN

Benign

-1.9

REVEL

Uncertain

0.33

Sift

Uncertain

0.016

Sift4G

Benign

0.26

Polyphen

1.0

Vest4

0.85

MutPred

0.41

Loss of catalytic residue at S868 (P = 0.0373)

MVP

0.59

MPC

0.71

ClinPred

0.82

GERP RS

5.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.32

gMVP

0.48

Mutation Taster

=13/87

disease causing

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over