Genetic Variant EFCAB6:p.Leu1000Val (chr22-43590108-G-C) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_022785.4(EFCAB6):c.2998C>G(p.Leu1000Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000212 in 1,461,796 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.000021 ( 0 hom. )

Consequence

EFCAB6
NM_022785.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.28

Publications

0 publications found

Variant links:

Genes affected

EFCAB6 (HGNC:24204): (EF-hand calcium binding domain 6) This gene encodes a protein which directly binds the oncogene DJ-1 and androgen receptor to form a ternary complex in cells. This binding protein recruits histone-deacetylase complexes in order to repress transcription activity of androgen receptor. This protein may also play a role in spermatogenesis and fertilization. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Sep 2011]

EFCAB6 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.24092296).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EFCAB6	NM_022785.4 link	c.2998C>G	p.Leu1000Val	missense_variant	Exon 24 of 32	ENST00000262726.12	NP_073622.2	Q5THR3-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
EFCAB6	ENST00000262726.12 link	c.2998C>G	p.Leu1000Val	missense_variant	Exon 24 of 32	2	NM_022785.4	ENSP00000262726.7	Q5THR3-1
EFCAB6	ENST00000396231.6 link	c.2542C>G	p.Leu848Val	missense_variant	Exon 22 of 30	1		ENSP00000379533.2	Q5THR3-2
EFCAB6	ENST00000468552.1 link	n.1447C>G		non_coding_transcript_exon_variant	Exon 10 of 13	1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.0000212

AC:

AN:

1461796

Hom.:

Cov.:

AF XY:

0.0000193

AC XY:

AN XY:

727190

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33478

American (AMR)

AF:

0.00

AC:

AN:

44716

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26130

East Asian (EAS)

AF:

0.00

AC:

AN:

39694

South Asian (SAS)

AF:

0.00

AC:

AN:

86238

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.0000270

AC:

AN:

1111962

Other (OTH)

AF:

0.0000166

AC:

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.472

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.:

Alfa

AF:

0.00

Hom.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

May 03, 2023

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.2998C>G (p.L1000V) alteration is located in exon 24 (coding exon 22) of the EFCAB6 gene. This alteration results from a C to G substitution at nucleotide position 2998, causing the leucine (L) at amino acid position 1000 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

0.12

BayesDel_addAF

Benign

0.00092

BayesDel_noAF

Benign

-0.24

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.015

.;T

Eigen

Benign

-0.20

Eigen_PC

Benign

-0.35

FATHMM_MKL

Benign

0.42

LIST_S2

Benign

0.68

T;T

M_CAP

Benign

0.053

MetaRNN

Benign

0.24

T;T

MetaSVM

Benign

-0.31

MutationAssessor

Uncertain

2.5

.;M

PhyloP100

1.3

PrimateAI

Benign

0.26

PROVEAN

Benign

-1.9

N;N

REVEL

Uncertain

0.38

Sift

Benign

0.17

T;T

Sift4G

Uncertain

0.021

D;D

Polyphen

0.98

D;P

Vest4

0.26

MutPred

0.46

.;Gain of catalytic residue at L1000 (P = 0.0105);

MVP

0.80

MPC

0.11

ClinPred

0.57

GERP RS

2.6

Varity_R

0.072

gMVP

0.16

Mutation Taster

=100/0

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over