2-26421396-C-T

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 16P and 5B. PVS1PP5_Very_StrongBS1_SupportingBS2

The NM_145038.5(DRC1):c.352C>T(p.Gln118*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000597 in 1,612,348 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.00028 ( 0 hom., cov: 31)

Exomes 𝑓: 0.00063 ( 2 hom. )

Consequence

DRC1
NM_145038.5 stop_gained

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:9U:1

Conservation

PhyloP100: 1.88

Publications

15 publications found

Variant links:

Genes affected

DRC1 (HGNC:24245): (dynein regulatory complex subunit 1) This gene encodes a central component of the nexin-dynein complex (N-DRC), which regulates the assembly of ciliary dynein. Mutations in this gene can cause ciliary dyskinesia. [provided by RefSeq, Aug 2015]

DRC1 Gene-Disease associations (from GenCC):

primary ciliary dyskinesia 21
Inheritance: AR Classification: STRONG, MODERATE, LIMITED Submitted by: Ambry Genetics, G2P, PanelApp Australia, Labcorp Genetics (formerly Invitae)
primary ciliary dyskinesia
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
spermatogenic failure 80
Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics

DRC1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 11 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

PP5

Variant 2-26421396-C-T is Pathogenic according to our data. Variant chr2-26421396-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 55840.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAdExome4 allele frequency = 0.000629 (919/1460280) while in subpopulation NFE AF = 0.000771 (857/1110948). AF 95% confidence interval is 0.000728. There are 2 homozygotes in GnomAdExome4. There are 449 alleles in the male GnomAdExome4 subpopulation. Median coverage is 29. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

BS2

High Homozygotes in GnomAdExome4 at 2 AR,AD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DRC1	NM_145038.5 link	c.352C>T	p.Gln118*	stop_gained	Exon 3 of 17	ENST00000288710.7	NP_659475.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DRC1	ENST00000288710.7 link	c.352C>T	p.Gln118*	stop_gained	Exon 3 of 17	2	NM_145038.5	ENSP00000288710.2

Frequencies

GnomAD3 genomes

AF:

0.000283

AC:

AN:

152068

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000725

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000415

Gnomad FIN

AF:

0.0000944

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000544

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000390

AC:

AN:

251328

AF XY:

0.000383

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000145

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000554

Gnomad NFE exome

AF:

0.000677

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.000629

AC:

919

AN:

1460280

Hom.:

Cov.:

AF XY:

0.000618

AC XY:

449

AN XY:

726476

show subpopulations

African (AFR)

AF:

0.000179

AC:

AN:

33440

American (AMR)

AF:

0.0000895

AC:

AN:

44678

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26092

East Asian (EAS)

AF:

0.00

AC:

AN:

39602

South Asian (SAS)

AF:

0.0000812

AC:

AN:

86182

European-Finnish (FIN)

AF:

0.000450

AC:

AN:

53294

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5762

European-Non Finnish (NFE)

AF:

0.000771

AC:

857

AN:

1110948

Other (OTH)

AF:

0.000348

AC:

AN:

60282

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.473

Heterozygous variant carriers

120

160

200

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

120

150

<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:

0.000283

AC:

AN:

152068

Hom.:

Cov.:

AF XY:

0.000242

AC XY:

AN XY:

74282

show subpopulations

African (AFR)

AF:

0.0000725

AC:

AN:

41406

American (AMR)

AF:

0.00

AC:

AN:

15254

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3466

East Asian (EAS)

AF:

0.00

AC:

AN:

5192

South Asian (SAS)

AF:

0.000415

AC:

AN:

4816

European-Finnish (FIN)

AF:

0.0000944

AC:

AN:

10592

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.000544

AC:

AN:

68020

Other (OTH)

AF:

0.00

AC:

AN:

2094

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.561

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:

0.000485

Hom.:

Bravo

AF:

0.000314

TwinsUK

AF:

0.000809

AC:

ALSPAC

AF:

0.000778

AC:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.000395

AC:

EpiCase

AF:

0.000600

EpiControl

AF:

0.000474

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:9Uncertain:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Primary ciliary dyskinesia 21

Pathogenic:3

May 23, 2023

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:research

- -

Mar 01, 2013

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Oct 31, 2018

Fulgent Genetics, Fulgent Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Pathogenic:2

Jun 02, 2022

GeneDx

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 27996046, 23354437, 30487145, 12746204, 26582918, 34426522, 27535533) -

Nov 13, 2015

Eurofins Ntd Llc (ga)

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Spermatogenic failure 80

Pathogenic:1

Apr 24, 2025

Clinical Genetics Laboratory, Skane University Hospital Lund

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

ACMG criteria used: PVS1, PM3 -

Primary ciliary dyskinesia;C3809087:Primary ciliary dyskinesia 21

Pathogenic:1

Laboratory of Cell Biology, Institute of Biomedical Sciences Abel Salazar (ICBAS)

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

We analyzed the expression of DRC1 of a patient with this mutation and observed that mRNA was downregulated as well as its protein were also decreased. -

Primary ciliary dyskinesia

Pathogenic:1

Dec 29, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change creates a premature translational stop signal (p.Gln118*) in the DRC1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in DRC1 are known to be pathogenic (PMID: 23354437, 31960620). This variant is present in population databases (rs142371860, gnomAD 0.07%), including at least one homozygous and/or hemizygous individual. This premature translational stop signal has been observed in individual(s) with primary ciliary dyskinesia (PMID: 23354437). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 55840). For these reasons, this variant has been classified as Pathogenic. -

DRC1-related disorder

Pathogenic:1

Jul 01, 2024

PreventionGenetics, part of Exact Sciences

Significance:Likely pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

The DRC1 c.352C>T variant is predicted to result in premature protein termination (p.Gln118*). This variant has been reported in the homozygous state in three affected individuals from two families with primary ciliary dyskinesia, and segregated with the disease in these families (Supplementary Figure 3, Wirschell et al. 2013. PubMed ID: 23354437). This variant is reported in 0.067% of alleles in individuals of European (Non-Finnish) descent in gnomAD, including 1 homozygote. Nonsense variants in DRC1 are expected to be pathogenic. This variant is interpreted as likely pathogenic. -

not specified

Uncertain:1

Mar 16, 2018

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Uncertain significance

Review Status:flagged submission

Collection Method:clinical testing

Variant classified as Uncertain Significance - Favor Pathogenic. The p.Gln118X ( NM145038.2 c.352C>T) variant in DRC1 has been previously reported in 2 homozygou s individuals with primary ciliary dyskinesia and segregated in 1 affected homoz ygous family member in 1 family (Wirschell 2013). Mutant studies and studies fro m patient cells with the p.Gln118X variant report an impact to protein function (Wirschell 2013). This variant has also been reported in ClinVar as likely patho genic (Variation ID#55840). It has been identified in 0.066% (83/126650) of Euro pean chromosomes by the Genome Aggregation Database (http://gnomad.broadinstitut e.org; rs142371860). Although this variant has been seen in the general populati on, its frequency is low enough to be consistent with a recessive carrier freque ncy. This nonsense variant leads to a premature termination codon at position 11 8, which is predicted to lead to a truncated or absent protein. In summary, ther e is suspicion for a pathogenic role; however, the gene-disease association bet ween DRC1 is currently assessed at a moderate level. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.37

BayesDel_noAF

Pathogenic

0.62

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

Eigen

Pathogenic

0.78

Eigen_PC

Uncertain

0.63

FATHMM_MKL

Uncertain

0.76

PhyloP100

1.9

Vest4

0.76

GERP RS

5.4

Mutation Taster

=11/189

disease causing (ClinVar)

(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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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