rs201260214

Positions:

chr2-26455142-C-G

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2BP4_StrongBP6

The NM_145038.5(DRC1):c.2075C>G(p.Thr692Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000447 in 1,614,048 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00036 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00046 ( 1 hom. )

Consequence

DRC1
NM_145038.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:1

Conservation

PhyloP100: 0.739

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 Likely_benign. Variant got -3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.014039427).

BP6

Variant 2-26455142-C-G is Benign according to our data. Variant chr2-26455142-C-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 525259.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DRC1	NM_145038.5 linkuse as main transcript	c.2075C>G	p.Thr692Ser	missense_variant	16/17	ENST00000288710.7	NP_659475.2	Q96MC2
DRC1	XM_047446339.1 linkuse as main transcript	c.1055C>G	p.Thr352Ser	missense_variant	9/10		XP_047302295.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
DRC1	ENST00000288710.7 linkuse as main transcript	c.2075C>G	p.Thr692Ser	missense_variant	16/17	2	NM_145038.5	ENSP00000288710.2	Q96MC2
DRC1	ENST00000649059.1 linkuse as main transcript	n.*1038C>G		non_coding_transcript_exon_variant	15/16			ENSP00000497543.1	A0A3B3IT12
DRC1	ENST00000649059.1 linkuse as main transcript	n.*1038C>G		3_prime_UTR_variant	15/16			ENSP00000497543.1	A0A3B3IT12

Frequencies

GnomAD3 genomes

AF:

0.000362

AC:

AN:

152072

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000242

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000393

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000415

Gnomad FIN

AF:

0.00179

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000397

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000330

AC:

AN:

251384

Hom.:

AF XY:

0.000316

AC XY:

AN XY:

135876

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000347

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000980

Gnomad FIN exome

AF:

0.00129

Gnomad NFE exome

AF:

0.000308

Gnomad OTH exome

AF:

0.000815

GnomAD4 exome

AF:

0.000456

AC:

666

AN:

1461858

Hom.:

Cov.:

AF XY:

0.000426

AC XY:

310

AN XY:

727232

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.000291

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000174

Gnomad4 FIN exome

AF:

0.00131

Gnomad4 NFE exome

AF:

0.000495

Gnomad4 OTH exome

AF:

0.000265

GnomAD4 genome

AF:

0.000361

AC:

AN:

152190

Hom.:

Cov.:

AF XY:

0.000363

AC XY:

AN XY:

74416

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.000392

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000415

Gnomad4 FIN

AF:

0.00179

Gnomad4 NFE

AF:

0.000397

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000236

Hom.:

Bravo

AF:

0.000276

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.000371

AC:

EpiCase

AF:

0.000164

EpiControl

AF:

0.000533

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 30, 2024

The c.2075C>G (p.T692S) alteration is located in exon 16 (coding exon 16) of the DRC1 gene. This alteration results from a C to G substitution at nucleotide position 2075, causing the threonine (T) at amino acid position 692 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Primary ciliary dyskinesia 21

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Sep 16, 2022

The DRC1 c.2075C>G; p.Thr692Ser variant (rs201260214), to our knowledge, is not reported in the medical literature but is reported in ClinVar (Variation ID: 525259). This variant is found in the general population with an allele frequency of 0.033% (92/282,772 alleles, including 1 homozygote) in the Genome Aggregation Database. The threonine at codon 692 is moderately conserved, but computational analyses predict that this variant is neutral (REVEL: 0.04). However, given the lack of clinical and functional data, the significance of the p.Thr692Ser variant is uncertain at this time. -

Primary ciliary dyskinesia

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Nov 24, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.088

BayesDel_addAF

Benign

-0.45

BayesDel_noAF

Benign

-0.57

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Benign

0.0047

Eigen

Benign

-0.40

Eigen_PC

Benign

-0.38

FATHMM_MKL

Benign

0.21

LIST_S2

Benign

0.46

M_CAP

Benign

0.0066

MetaRNN

Benign

0.014

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.9

PrimateAI

Benign

0.41

PROVEAN

Benign

-1.8

REVEL

Benign

0.040

Sift

Benign

0.22

Sift4G

Benign

0.24

Polyphen

0.25

Vest4

0.14

MutPred

0.45

Gain of disorder (P = 0.0599);

MVP

0.30

MPC

0.073

ClinPred

0.023

GERP RS

1.3

Varity_R

0.15

gMVP

0.15

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