Genetic Variant EFCAB12:p.Arg58Gln (chr3-129421680-C-T) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_207307.3(EFCAB12):c.173G>A(p.Arg58Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000434 in 1,613,842 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000045 ( 0 hom. )

Consequence

EFCAB12
NM_207307.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.90

Publications

4 publications found

Variant links:

Genes affected

EFCAB12 (HGNC:28061): (EF-hand calcium binding domain 12) Predicted to enable calcium ion binding activity. [provided by Alliance of Genome Resources, Apr 2022]

EFCAB12 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.20475188).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EFCAB12	NM_207307.3 link	c.173G>A	p.Arg58Gln	missense_variant	Exon 2 of 9	ENST00000505956.6	NP_997190.1	Q6NXP0B3KXU6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
EFCAB12	ENST00000505956.6 link	c.173G>A	p.Arg58Gln	missense_variant	Exon 2 of 9	1	NM_207307.3	ENSP00000420854.1	Q6NXP0
EFCAB12	ENST00000503957.1 link	c.37-3232G>A		intron_variant	Intron 1 of 3	5		ENSP00000421462.1	D6RFI2
EFCAB12	ENST00000503498.1 link	n.-97G>A		upstream_gene_variant		2

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152118

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000770

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000803

AC:

AN:

249052

AF XY:

0.000104

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000278

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000266

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000452

AC:

AN:

1461606

Hom.:

Cov.:

AF XY:

0.0000454

AC XY:

AN XY:

727092

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.0000224

AC:

AN:

44718

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26132

East Asian (EAS)

AF:

0.000605

AC:

AN:

39698

South Asian (SAS)

AF:

0.000290

AC:

AN:

86244

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53338

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0000126

AC:

AN:

1111854

Other (OTH)

AF:

0.0000331

AC:

AN:

60374

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.477

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:

0.0000263

AC:

AN:

152236

Hom.:

Cov.:

AF XY:

0.0000403

AC XY:

AN XY:

74432

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41546

American (AMR)

AF:

0.00

AC:

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.000772

AC:

AN:

5182

South Asian (SAS)

AF:

0.00

AC:

AN:

4810

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10598

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68016

Other (OTH)

AF:

0.00

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.513

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome 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

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000491

ExAC

AF:

0.000108

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Mar 07, 2024

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.173G>A (p.R58Q) alteration is located in exon 2 (coding exon 2) of the EFCAB12 gene. This alteration results from a G to A substitution at nucleotide position 173, causing the arginine (R) at amino acid position 58 to be replaced by a glutamine (Q). 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

0.23

BayesDel_addAF

Benign

-0.33

BayesDel_noAF

Benign

-0.40

CADD

Uncertain

(source)

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.017

T;T

Eigen

Uncertain

0.22

Eigen_PC

Benign

0.14

FATHMM_MKL

Benign

0.43

LIST_S2

Benign

0.84

.;T

M_CAP

Benign

0.0067

MetaRNN

Benign

0.20

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

2.0

M;M

PhyloP100

2.9

PrimateAI

Benign

0.34

PROVEAN

Uncertain

-2.9

D;D

REVEL

Benign

0.13

Sift

Uncertain

0.018

D;D

Sift4G

Uncertain

0.055

T;T

Polyphen

1.0

D;D

Vest4

0.56

MutPred

0.47

Loss of MoRF binding (P = 0.0345);Loss of MoRF binding (P = 0.0345);

MVP

0.56

MPC

0.41

ClinPred

0.42

GERP RS

4.0

Varity_R

0.19

gMVP

0.53

Mutation Taster

=94/6

polymorphism

(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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over