Genetic Variant NM_001143943.1:c.392G>A (chr1-245121938-G-A) – ACMG Classification: Benign (-10 pts)

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_StrongBP6_ModerateBS2

The NM_001143943.1(DRC8):c.392G>A(p.Arg131His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00669 in 413,916 control chromosomes in the GnomAD database, including 16 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/17 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.0067 ( 6 hom., cov: 32)

Exomes 𝑓: 0.0067 ( 10 hom. )

Consequence

DRC8
NM_001143943.1 missense

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: -2.31

Publications

1 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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -10 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.006601095).

BP6

Variant 1-245121938-G-A is Benign according to our data. Variant chr1-245121938-G-A is described in ClinVar as Likely_benign. ClinVar VariationId is 3770774.Status of the report is criteria_provided_single_submitter, 1 stars.

BS2

High Homozygotes in GnomAd4 at 6 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001143943.1. 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
	DRC8	NM_001143943.1		c.392G>A	p.Arg131His	missense	Exon 7 of 7	NP_001137415.1	Q5VUJ9-3
	DRC8	NR_026587.1		n.397G>A		non_coding_transcript_exon	Exon 6 of 6

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
EFCAB2	ENST00000447569.6	TSL:2	c.392G>A	p.Arg131His	missense	Exon 7 of 7	ENSP00000408661.2	Q5VUJ9-3
EFCAB2	ENST00000366522.6	TSL:2	n.941G>A		non_coding_transcript_exon	Exon 8 of 8
EFCAB2	ENST00000479923.1	TSL:2	n.138G>A		non_coding_transcript_exon	Exon 2 of 2

Frequencies

GnomAD3 genomes

AF:

0.00668

AC:

1007

AN:

150644

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00449

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00544

Gnomad ASJ

AF:

0.00722

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00231

Gnomad FIN

AF:

0.00222

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.00991

Gnomad OTH

AF:

0.00484

GnomAD2 exomes

AF:

0.00576

AC:

601

AN:

104360

AF XY:

0.00560

show subpopulations

Gnomad AFR exome

AF:

0.00335

Gnomad AMR exome

AF:

0.00442

Gnomad ASJ exome

AF:

0.00704

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00243

Gnomad NFE exome

AF:

0.00945

Gnomad OTH exome

AF:

0.00506

GnomAD4 exome

AF:

0.00671

AC:

1766

AN:

263154

Hom.:

Cov.:

AF XY:

0.00630

AC XY:

958

AN XY:

152040

show subpopulations

African (AFR)

AF:

0.00342

AC:

AN:

5848

American (AMR)

AF:

0.00405

AC:

AN:

19254

Ashkenazi Jewish (ASJ)

AF:

0.00837

AC:

AN:

9554

East Asian (EAS)

AF:

0.00

AC:

AN:

7888

South Asian (SAS)

AF:

0.00231

AC:

118

AN:

51104

European-Finnish (FIN)

AF:

0.00142

AC:

AN:

11234

Middle Eastern (MID)

AF:

0.00427

AC:

AN:

936

European-Non Finnish (NFE)

AF:

0.00952

AC:

1383

AN:

145278

Other (OTH)

AF:

0.00556

AC:

AN:

12058

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.483

Heterozygous variant carriers

151

226

302

377

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:

0.00667

AC:

1005

AN:

150762

Hom.:

Cov.:

AF XY:

0.00646

AC XY:

475

AN XY:

73530

show subpopulations

African (AFR)

AF:

0.00448

AC:

183

AN:

40852

American (AMR)

AF:

0.00543

AC:

AN:

15102

Ashkenazi Jewish (ASJ)

AF:

0.00722

AC:

AN:

3464

East Asian (EAS)

AF:

0.00

AC:

AN:

5146

South Asian (SAS)

AF:

0.00231

AC:

AN:

4760

European-Finnish (FIN)

AF:

0.00222

AC:

AN:

10366

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00990

AC:

671

AN:

67786

Other (OTH)

AF:

0.00479

AC:

AN:

2088

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.495

Heterozygous variant carriers

111

167

222

278

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<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:

0.00852

Hom.:

Bravo

AF:

0.00656

TwinsUK

AF:

0.00863

AC:

ALSPAC

AF:

0.00882

AC:

ExAC

AF:

0.00285

AC:

Asia WGS

AF:

0.000866

AC:

AN:

3478

ClinVar

ClinVar submissions

Significance:Likely benign

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.081

BayesDel_addAF

Benign

-0.43

BayesDel_noAF

Benign

-0.38

CADD

Benign

0.057

(source)

DANN

Benign

0.69

DEOGEN2

Benign

0.0051

Eigen

Benign

-1.7

Eigen_PC

Benign

-1.8

FATHMM_MKL

Benign

0.0025

LIST_S2

Benign

0.35

MetaRNN

Benign

0.0066

MetaSVM

Benign

-0.96

PhyloP100

-2.3

PROVEAN

Benign

-0.67

REVEL

Benign

0.18

Sift

Pathogenic

0.0

Sift4G

Uncertain

0.0070

Polyphen

0.0010

Vest4

0.017

MVP

0.41

ClinPred

0.011

GERP RS

-0.32

Varity_R

0.074

Mutation Taster

=100/0

polymorphism

(source)

Splicing

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

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over