Genetic Variant EFCAB9:p.Arg155Cys (chr5-172203214-C-T) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 4P and 1B. PM1PM2BP4

The NM_001171183.2(EFCAB9):c.463C>T(p.Arg155Cys) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000332 in 1,505,782 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/26 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000022 ( 0 hom. )

Consequence

EFCAB9
NM_001171183.2 missense, splice_region

Scores

Splicing: ADA: 0.06539

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.32

Publications

0 publications found

Variant links:

Genes affected

EFCAB9 (HGNC:34530): (EF-hand calcium binding domain 9) This gene encodes a protein with a C-terminal EF-hand calcium-binding domain similar to that found in penta-EF-hand (PEF) protein family members. The EF-hand is a helix-loop-helix structure with a canonical twelve-residue sequence that coordinates a calcium molecule with pentagonal bipyramidal symmetry. [provided by RefSeq, Jul 2017]

EFCAB9 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

PM1

In a binding_site (size 0) in uniprot entity EFCB9_HUMAN

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.28070295).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001171183.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EFCAB9	NM_001171183.2	MANE Select	c.463C>T	p.Arg155Cys	missense splice_region	Exon 4 of 4	NP_001164654.1	A8MZ26

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EFCAB9	ENST00000398186.5	TSL:3 MANE Select	c.463C>T	p.Arg155Cys	missense splice_region	Exon 4 of 4	ENSP00000381247.4	A8MZ26

Frequencies

GnomAD3 genomes

AF:

0.0000132

AC:

AN:

151582

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000243

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:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.000481

GnomAD4 exome

AF:

0.00000222

AC:

AN:

1354200

Hom.:

Cov.:

AF XY:

0.00000300

AC XY:

AN XY:

667630

show subpopulations

African (AFR)

AF:

0.0000333

AC:

AN:

29996

American (AMR)

AF:

0.00

AC:

AN:

29532

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

23882

East Asian (EAS)

AF:

0.00

AC:

AN:

35316

South Asian (SAS)

AF:

0.00

AC:

AN:

73988

European-Finnish (FIN)

AF:

0.00

AC:

AN:

34124

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5518

European-Non Finnish (NFE)

AF:

0.00000188

AC:

AN:

1065350

Other (OTH)

AF:

0.00

AC:

AN:

56494

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

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

AF:

0.0000132

AC:

AN:

151582

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

73980

show subpopulations

African (AFR)

AF:

0.0000243

AC:

AN:

41170

American (AMR)

AF:

0.00

AC:

AN:

15206

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5178

South Asian (SAS)

AF:

0.00

AC:

AN:

4816

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10472

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

67964

Other (OTH)

AF:

0.000481

AC:

AN:

2078

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.550

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000113

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.095

BayesDel_addAF

Benign

-0.079

BayesDel_noAF

Benign

-0.35

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.18

Eigen

Uncertain

0.31

Eigen_PC

Benign

0.22

FATHMM_MKL

Uncertain

0.82

LIST_S2

Benign

0.76

M_CAP

Benign

0.022

MetaRNN

Benign

0.28

MetaSVM

Benign

-0.95

MutationAssessor

Benign

2.0

PhyloP100

1.3

PrimateAI

Benign

0.31

PROVEAN

Uncertain

-4.0

REVEL

Benign

0.12

Sift

Uncertain

0.022

Sift4G

Uncertain

0.012

Vest4

0.15

MutPred

0.33

Loss of disorder (P = 0.1109)

MVP

0.53

ClinPred

0.98

GERP RS

5.0

Varity_R

0.11

gMVP

0.31

Mutation Taster

=73/27

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.065

dbscSNV1_RF

Benign

0.44

SpliceAI score (max)

0.20

Details are displayed if max score is > 0.2

DS_AL_spliceai

0.20

Position offset: 0

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