rs139583194

Positions:

chr2-26424335-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_145038.5(DRC1):c.421T>G(p.Trp141Gly) variant causes a missense change. The variant allele was found at a frequency of 0.000399 in 1,613,342 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.00025 ( 0 hom., cov: 31)

Exomes 𝑓: 0.00041 ( 0 hom. )

Consequence

DRC1
NM_145038.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:3

Conservation

PhyloP100: 7.01

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DRC1	NM_145038.5 linkuse as main transcript	c.421T>G	p.Trp141Gly	missense_variant	4/17	ENST00000288710.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DRC1	ENST00000288710.7 linkuse as main transcript	c.421T>G	p.Trp141Gly	missense_variant	4/17	2	NM_145038.5	P1

Frequencies

GnomAD3 genomes

AF:

0.000251

AC:

AN:

151340

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000973

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000396

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000418

Gnomad FIN

AF:

0.0000955

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000354

Gnomad OTH

AF:

0.000481

GnomAD3 exomes

AF:

0.000239

AC:

AN:

251384

Hom.:

AF XY:

0.000309

AC XY:

AN XY:

135852

show subpopulations

Gnomad AFR exome

AF:

0.0000615

Gnomad AMR exome

AF:

0.0000578

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000621

Gnomad FIN exome

AF:

0.0000924

Gnomad NFE exome

AF:

0.000308

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.000415

AC:

606

AN:

1461884

Hom.:

Cov.:

AF XY:

0.000400

AC XY:

291

AN XY:

727238

show subpopulations

Gnomad4 AFR exome

AF:

0.0000597

Gnomad4 AMR exome

AF:

0.0000671

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000696

Gnomad4 FIN exome

AF:

0.0000749

Gnomad4 NFE exome

AF:

0.000455

Gnomad4 OTH exome

AF:

0.000513

GnomAD4 genome

AF:

0.000251

AC:

AN:

151458

Hom.:

Cov.:

AF XY:

0.000230

AC XY:

AN XY:

73998

show subpopulations

Gnomad4 AFR

AF:

0.0000970

Gnomad4 AMR

AF:

0.000395

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000418

Gnomad4 FIN

AF:

0.0000955

Gnomad4 NFE

AF:

0.000354

Gnomad4 OTH

AF:

0.000476

Alfa

AF:

0.000292

Hom.:

Bravo

AF:

0.000257

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000778

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000581

AC:

ExAC

AF:

0.000239

AC:

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.000491

EpiControl

AF:

0.000178

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Primary ciliary dyskinesia 21

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Neuberg Centre For Genomic Medicine, NCGM	-	The missense c.421T>Gp.Trp141Gly variant in DRC1 gene has been reported in an individual affected with primary ciliary dyskinesia Olm MAK, et. al., 2019. The p.Trp141Gly variant has been reported with allele frequency of 0.02% in gnomAD Exomes and is novel not in any individuals in 1000 Genomes database. This variant has been reported to the ClinVar database as Uncertain significance. The amino acid change p.Trp141Gly in DRC1 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. The amino acid Trp at position 141 is changed to a Gly changing protein sequence and it might alter its composition and physico-chemical properties. For these reasons, this variant has been classified as Variant of Uncertain Significance VUS. -
Uncertain significance, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Apr 11, 2022	- -

Primary ciliary dyskinesia

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Oct 01, 2022

This sequence change replaces tryptophan, which is neutral and slightly polar, with glycine, which is neutral and non-polar, at codon 141 of the DRC1 protein (p.Trp141Gly). This variant is present in population databases (rs139583194, gnomAD 0.06%). This missense change has been observed in individual(s) with primary ciliary dyskinesia (PMID: 31213628). ClinVar contains an entry for this variant (Variation ID: 407099). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.93

BayesDel_addAF

Uncertain

0.028

BayesDel_noAF

Pathogenic

0.16

CADD

Pathogenic

DANN

Uncertain

0.98

DEOGEN2

Benign

0.37

Eigen

Pathogenic

0.82

Eigen_PC

Pathogenic

0.76

FATHMM_MKL

Uncertain

0.95

LIST_S2

Benign

0.71

M_CAP

Benign

0.041

MetaRNN

Uncertain

0.71

MetaSVM

Benign

-0.37

MutationAssessor

Pathogenic

3.3

MutationTaster

Benign

1.0

PrimateAI

Uncertain

0.58

PROVEAN

Pathogenic

-11

REVEL

Uncertain

0.53

Sift

Pathogenic

0.0

Sift4G

Benign

0.089

Polyphen

1.0

Vest4

0.92

MVP

0.62

MPC

0.47

ClinPred

0.95

GERP RS

5.5

Varity_R

0.97

gMVP

0.67

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