2-26448712-C-T

Position:

chr2-26448712-C-T

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4_StrongBS1_Supporting

The NM_145038.5(DRC1):c.1418C>T(p.Ala473Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000237 in 1,614,200 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.00034 ( 1 hom., cov: 33)

Exomes 𝑓: 0.00023 ( 1 hom. )

Consequence

DRC1
NM_145038.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:5B:1

Conservation

PhyloP100: -1.94

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 -5 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.010977119).

BS1

Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.000226 (331/1461868) while in subpopulation MID AF= 0.00781 (45/5760). AF 95% confidence interval is 0.006. There are 1 homozygotes in gnomad4_exome. There are 174 alleles in male gnomad4_exome subpopulation. Median coverage is 33. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DRC1	NM_145038.5 linkuse as main transcript	c.1418C>T	p.Ala473Val	missense_variant	11/17	ENST00000288710.7	NP_659475.2
DRC1	XM_047446339.1 linkuse as main transcript	c.398C>T	p.Ala133Val	missense_variant	4/10		XP_047302295.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris
DRC1	ENST00000288710.7 linkuse as main transcript	c.1418C>T	p.Ala473Val	missense_variant	11/17	2	NM_145038.5	ENSP00000288710	P1
DRC1	ENST00000439066.2 linkuse as main transcript	n.148C>T		non_coding_transcript_exon_variant	2/5	3
DRC1	ENST00000649059.1 linkuse as main transcript	c.*381C>T		3_prime_UTR_variant, NMD_transcript_variant	10/16			ENSP00000497543

Frequencies

GnomAD3 genomes

AF:

0.000335

AC:

AN:

152214

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000965

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000654

Gnomad ASJ

AF:

0.000864

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0000942

Gnomad MID

AF:

0.0158

Gnomad NFE

AF:

0.000367

Gnomad OTH

AF:

0.00143

GnomAD3 exomes

AF:

0.000290

AC:

AN:

251452

Hom.:

AF XY:

0.000294

AC XY:

AN XY:

135916

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000231

Gnomad ASJ exome

AF:

0.00218

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000980

Gnomad FIN exome

AF:

0.000185

Gnomad NFE exome

AF:

0.000281

Gnomad OTH exome

AF:

0.000652

GnomAD4 exome

AF:

0.000226

AC:

331

AN:

1461868

Hom.:

Cov.:

AF XY:

0.000239

AC XY:

174

AN XY:

727228

show subpopulations

Gnomad4 AFR exome

AF:

0.000508

Gnomad4 AMR exome

AF:

0.000313

Gnomad4 ASJ exome

AF:

0.00126

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000128

Gnomad4 FIN exome

AF:

0.000131

Gnomad4 NFE exome

AF:

0.000151

Gnomad4 OTH exome

AF:

0.000596

GnomAD4 genome

AF:

0.000341

AC:

AN:

152332

Hom.:

Cov.:

AF XY:

0.000336

AC XY:

AN XY:

74496

show subpopulations

Gnomad4 AFR

AF:

0.0000962

Gnomad4 AMR

AF:

0.000653

Gnomad4 ASJ

AF:

0.000864

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.0000942

Gnomad4 NFE

AF:

0.000367

Gnomad4 OTH

AF:

0.00142

Alfa

AF:

0.000398

Hom.:

Bravo

AF:

0.000310

ExAC

AF:

0.000338

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.000273

EpiControl

AF:

0.000652

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:5Benign:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Aug 21, 2017	The A473V variant in the DRC1 gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. The A473V variant is observed in 29/66,340 (0.043%) alleles from individuals of European (non-Finnish) background in the ExAC dataset (Lek et al., 2016). The A473V variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. This substitution occurs at a position that is not conserved, and in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. We interpret A473V as a variant of uncertain significance. -
Uncertain significance, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 27, 2022

The c.1418C>T (p.A473V) alteration is located in exon 11 (coding exon 11) of the DRC1 gene. This alteration results from a C to T substitution at nucleotide position 1418, causing the alanine (A) at amino acid position 473 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Primary ciliary dyskinesia

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Aug 09, 2022

This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 473 of the DRC1 protein (p.Ala473Val). This variant is present in population databases (rs199574440, gnomAD 0.2%). This variant has not been reported in the literature in individuals affected with DRC1-related conditions. ClinVar contains an entry for this variant (Variation ID: 407102). 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 tolerated. 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. -

Primary ciliary dyskinesia 21

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Jan 04, 2022

- -

DRC1-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 06, 2023

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.085

BayesDel_addAF

Benign

-0.46

BayesDel_noAF

Benign

-0.59

CADD

Benign

0.32

DANN

Uncertain

0.99

DEOGEN2

Benign

0.0020

Eigen

Benign

-0.82

Eigen_PC

Benign

-0.95

FATHMM_MKL

Benign

0.054

LIST_S2

Benign

0.48

M_CAP

Benign

0.0054

MetaRNN

Benign

0.011

MetaSVM

Benign

-0.98

MutationAssessor

Uncertain

2.6

MutationTaster

Benign

1.0

PrimateAI

Benign

0.25

PROVEAN

Benign

-1.4

REVEL

Benign

0.075

Sift

Uncertain

0.026

Sift4G

Benign

0.12

Polyphen

0.22

Vest4

0.26

MVP

0.12

MPC

0.093

ClinPred

0.021

GERP RS

-0.71

Varity_R

0.059

gMVP

0.22

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