Genetic Variant DRC8:p.Phe73Leu (chr1-245082118-C-A) – 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_032328.4(DRC8):c.219C>A(p.Phe73Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,460,430 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. F73F) has been classified as Benign.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

DRC8
NM_032328.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.0370

Publications

0 publications found

Variant links:

Genes affected

DRC8 (HGNC:28166): (EF-hand calcium binding domain 2) The gene encodes a protein that contains two EF-hand calcium-binding domains although its function has yet to be determined. Alternatively spliced transcripts have been observed. [provided by RefSeq, Mar 2014]

DRC8 links:

ENSG00000305254 (HGNC:):

ENSG00000305254 links:

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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=0.15933412).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_032328.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
DRC8	NM_032328.4	MANE Select	c.219C>A	p.Phe73Leu	missense	Exon 5 of 8	NP_115704.1	Q5VUJ9-2
DRC8	NM_001290327.2		c.249C>A	p.Phe83Leu	missense	Exon 5 of 8	NP_001277256.1
DRC8	NM_001143943.1		c.219C>A	p.Phe73Leu	missense	Exon 4 of 7	NP_001137415.1	Q5VUJ9-3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
EFCAB2	ENST00000366523.6	TSL:3 MANE Select	c.219C>A	p.Phe73Leu	missense	Exon 5 of 8	ENSP00000355480.1	Q5VUJ9-2
EFCAB2	ENST00000948553.1		c.345C>A	p.Phe115Leu	missense	Exon 5 of 8	ENSP00000618612.1
EFCAB2	ENST00000923178.1		c.219C>A	p.Phe73Leu	missense	Exon 4 of 7	ENSP00000593237.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.85e-7

AC:

AN:

1460430

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

726626

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

33464

American (AMR)

AF:

0.00

AC:

AN:

44692

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26116

East Asian (EAS)

AF:

0.00

AC:

AN:

39690

South Asian (SAS)

AF:

0.00

AC:

AN:

86188

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53414

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5764

European-Non Finnish (NFE)

AF:

9.00e-7

AC:

AN:

1110728

Other (OTH)

AF:

0.00

AC:

AN:

60374

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.275

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

Pathogenic

0.95

BayesDel_addAF

Uncertain

0.022

BayesDel_noAF

Benign

-0.21

CADD

Benign

3.2

(source)

DANN

Benign

0.82

DEOGEN2

Benign

0.047

Eigen

Benign

-0.38

Eigen_PC

Benign

-0.37

FATHMM_MKL

Benign

0.089

LIST_S2

Benign

0.76

M_CAP

Benign

0.033

MetaRNN

Benign

0.16

MetaSVM

Benign

-0.99

PhyloP100

0.037

PrimateAI

Benign

0.46

PROVEAN

Benign

-1.4

REVEL

Uncertain

0.39

Sift

Benign

1.0

Sift4G

Benign

0.67

Polyphen

0.0010

Vest4

0.20

MutPred

0.66

Loss of ubiquitination at K211 (P = 0.1216)

MVP

0.90

MPC

0.16

ClinPred

0.23

GERP RS

0.79

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.053

gMVP

0.31

Mutation Taster

=89/11

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over