Genetic Variant EFCAB9:p.Arg146Cys (chr5-172200716-C-T) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001171183.2(EFCAB9):c.436C>T(p.Arg146Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000794 in 1,385,152 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/20 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: 0.0000079 ( 0 hom. )

Consequence

EFCAB9
NM_001171183.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.553

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 made for transcript

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=0.08427268).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EFCAB9	NM_001171183.2 link	c.436C>T	p.Arg146Cys	missense_variant	Exon 3 of 4	ENST00000398186.5	NP_001164654.1	A8MZ26

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EFCAB9	ENST00000398186.5 link	c.436C>T	p.Arg146Cys	missense_variant	Exon 3 of 4	3	NM_001171183.2	ENSP00000381247.4		A8MZ26

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000209

AC:

AN:

143286

Hom.:

AF XY:

0.0000262

AC XY:

AN XY:

76288

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000283

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000794

AC:

AN:

1385152

Hom.:

Cov.:

AF XY:

0.00000878

AC XY:

AN XY:

683490

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000280

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000840

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000556

Gnomad4 OTH exome

AF:

0.0000172

GnomAD4 genome

Cov.:

Bravo

AF:

0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

May 31, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.436C>T (p.R146C) alteration is located in exon 3 (coding exon 3) of the EFCAB9 gene. This alteration results from a C to T substitution at nucleotide position 436, causing the arginine (R) at amino acid position 146 to be replaced by a cysteine (C). 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

0.083

BayesDel_addAF

Benign

-0.43

BayesDel_noAF

Benign

-0.55

CADD

Benign

8.4

DANN

Benign

0.62

DEOGEN2

Benign

0.20

Eigen

Benign

-0.77

Eigen_PC

Benign

-0.91

FATHMM_MKL

Benign

0.052

LIST_S2

Benign

0.24

M_CAP

Benign

0.014

MetaRNN

Benign

0.084

MetaSVM

Benign

-0.97

MutationAssessor

Benign

0.20

PrimateAI

Benign

0.35

PROVEAN

Uncertain

-3.0

REVEL

Benign

0.023

Sift

Benign

0.15

Sift4G

Benign

0.24

Vest4

0.096

MutPred

0.38

Loss of catalytic residue at R146 (P = 0.0154);

MVP

0.37

ClinPred

0.12

GERP RS

-0.37

Varity_R

0.12

gMVP

0.22

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over