Genetic Variant DRC12:p.Arg53Cys (chr11-119193865-G-A) – 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_001145018.3(DRC12):c.157C>T(p.Arg53Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000213 in 1,551,316 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R53H) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000053 ( 0 hom., cov: 31)

Exomes 𝑓: 0.000018 ( 0 hom. )

Consequence

DRC12
NM_001145018.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.26

Publications

0 publications found

Variant links:

Genes affected

DRC12 (HGNC:27446): (dynein regulatory complex subunit 12 homolog) Enables identical protein binding activity. [provided by Alliance of Genome Resources, Apr 2022]

DRC12 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=0.10143769).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DRC12	NM_001145018.3 link	c.157C>T	p.Arg53Cys	missense_variant	Exon 4 of 7	ENST00000503566.7	NP_001138490.1	Q494R4-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
DRC12	ENST00000503566.7 link	c.157C>T	p.Arg53Cys	missense_variant	Exon 4 of 7	5	NM_001145018.3	ENSP00000423567.2	Q494R4-1
DRC12	ENST00000415318.2 link	c.157C>T	p.Arg53Cys	missense_variant	Exon 5 of 8	5		ENSP00000445431.1	Q494R4-1
DRC12	ENST00000375140.7 link	n.653C>T		non_coding_transcript_exon_variant	Exon 5 of 7	5

Frequencies

GnomAD3 genomes

AF:

0.0000526

AC:

AN:

152054

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000193

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:

0.00

GnomAD2 exomes

AF:

0.0000519

AC:

AN:

154036

AF XY:

0.0000245

show subpopulations

Gnomad AFR exome

AF:

0.000504

Gnomad AMR exome

AF:

0.0000810

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000168

Gnomad OTH exome

AF:

0.000230

GnomAD4 exome

AF:

0.0000179

AC:

AN:

1399262

Hom.:

Cov.:

AF XY:

0.0000130

AC XY:

AN XY:

690146

show subpopulations

African (AFR)

AF:

0.000222

AC:

AN:

31598

American (AMR)

AF:

0.0000560

AC:

AN:

35704

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25180

East Asian (EAS)

AF:

0.00

AC:

AN:

35736

South Asian (SAS)

AF:

0.00

AC:

AN:

79236

European-Finnish (FIN)

AF:

0.00

AC:

AN:

49164

Middle Eastern (MID)

AF:

0.000176

AC:

AN:

5698

European-Non Finnish (NFE)

AF:

0.0000111

AC:

AN:

1078948

Other (OTH)

AF:

0.0000517

AC:

AN:

57998

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

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:

0.0000526

AC:

AN:

152054

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74250

show subpopulations

African (AFR)

AF:

0.000193

AC:

AN:

41398

American (AMR)

AF:

0.00

AC:

AN:

15248

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5192

South Asian (SAS)

AF:

0.00

AC:

AN:

4820

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10588

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68018

Other (OTH)

AF:

0.00

AC:

AN:

2090

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.413

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:

0.0000658

Hom.:

Bravo

AF:

0.0000680

ExAC

AF:

0.0000410

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Nov 30, 2021

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.157C>T (p.R53C) alteration is located in exon 4 (coding exon 3) of the CCDC153 gene. This alteration results from a C to T substitution at nucleotide position 157, causing the arginine (R) at amino acid position 53 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

0.17

BayesDel_addAF

Benign

-0.38

BayesDel_noAF

Benign

-0.44

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.087

T;T

Eigen

Benign

-0.23

Eigen_PC

Benign

-0.15

FATHMM_MKL

Benign

0.67

LIST_S2

Benign

0.80

.;T

M_CAP

Benign

0.012

MetaRNN

Benign

0.10

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Uncertain

2.2

M;M

PhyloP100

1.3

PrimateAI

Benign

0.40

PROVEAN

Uncertain

-4.0

D;D

REVEL

Benign

0.038

Sift

Benign

0.054

T;T

Sift4G

Benign

0.069

T;T

Polyphen

0.20

B;B

Vest4

0.23

MVP

0.39

MPC

0.26

ClinPred

0.062

GERP RS

3.7

Varity_R

0.095

gMVP

0.23

Mutation Taster

=100/0

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.070

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