NM_145038.5:c.1897G>T

Variant names:

• chr2-26453527-G-T
• rs12623642
• NM_145038.5:c.1897G>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_145038.5(DRC1):​c.1897G>T​(p.Val633Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0918 in 1,613,792 control chromosomes in the GnomAD database, including 15,805 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V633I) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.093 (1713 hom., cov: 32)
  • Exomes 𝑓: 0.092 (14092 hom.)
• Consequence: DRC1 NM_145038.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 2.41
• Publications: 26 publications found

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

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=6.532371E-4).
• BP6: Variant 2-26453527-G-T is Benign according to our data. Variant chr2-26453527-G-T is described in ClinVar as Benign. ClinVar VariationId is 402798.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.576 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_145038.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DRC1	NM_145038.5	MANE Select	c.1897G>T	p.Val633Phe	missense	Exon 14 of 17	NP_659475.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DRC1	ENST00000288710.7	TSL:2 MANE Select	c.1897G>T	p.Val633Phe	missense	Exon 14 of 17	ENSP00000288710.2
	DRC1	ENST00000649059.1		n.*860G>T		non_coding_transcript_exon	Exon 13 of 16	ENSP00000497543.1
	DRC1	ENST00000649059.1		n.*860G>T		3_prime_UTR	Exon 13 of 16	ENSP00000497543.1

Frequencies

GnomAD3 genomes AF: 0.0934 AC: 14209 AN: 152090 Hom.: 1711 Cov.: 32

Gnomad AFR AF: 0.0337

Gnomad AMI AF: 0.0844

Gnomad AMR AF: 0.235

Gnomad ASJ AF: 0.0876

Gnomad EAS AF: 0.594

Gnomad SAS AF: 0.101

Gnomad FIN AF: 0.0515

Gnomad MID AF: 0.0285

Gnomad NFE AF: 0.0670

Gnomad OTH AF: 0.0881

GnomAD2 exomes AF: 0.145 AC: 36098 AN: 248512 AF XY: 0.132

Gnomad AFR exome AF: 0.0330

Gnomad AMR exome AF: 0.355

Gnomad ASJ exome AF: 0.0857

Gnomad EAS exome AF: 0.587

Gnomad FIN exome AF: 0.0516

Gnomad NFE exome AF: 0.0634

Gnomad OTH exome AF: 0.102

GnomAD4 exome AF: 0.0916 AC: 133916 AN: 1461588 Hom.: 14092 Cov.: 32 AF XY: 0.0905 AC XY: 65772 AN XY: 727074

African (AFR) AF: 0.0279 AC: 934 AN: 33474

American (AMR) AF: 0.338 AC: 15079 AN: 44662

Ashkenazi Jewish (ASJ) AF: 0.0904 AC: 2362 AN: 26128

East Asian (EAS) AF: 0.615 AC: 24399 AN: 39684

South Asian (SAS) AF: 0.0971 AC: 8372 AN: 86228

European-Finnish (FIN) AF: 0.0519 AC: 2773 AN: 53402

Middle Eastern (MID) AF: 0.0537 AC: 309 AN: 5758

European-Non Finnish (NFE) AF: 0.0662 AC: 73627 AN: 1111874

Other (OTH) AF: 0.100 AC: 6061 AN: 60378

GnomAD4 genome AF: 0.0934 AC: 14216 AN: 152204 Hom.: 1713 Cov.: 32 AF XY: 0.0982 AC XY: 7305 AN XY: 74408

African (AFR) AF: 0.0337 AC: 1400 AN: 41532

American (AMR) AF: 0.235 AC: 3590 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.0876 AC: 304 AN: 3470

East Asian (EAS) AF: 0.593 AC: 3061 AN: 5158

South Asian (SAS) AF: 0.101 AC: 487 AN: 4830

European-Finnish (FIN) AF: 0.0515 AC: 546 AN: 10610

Middle Eastern (MID) AF: 0.0306 AC: 9 AN: 294

European-Non Finnish (NFE) AF: 0.0670 AC: 4558 AN: 68014

Other (OTH) AF: 0.0872 AC: 184 AN: 2110

Alfa AF: 0.0841 Hom.: 4640

Bravo AF: 0.110

TwinsUK AF: 0.0607 AC: 225

ALSPAC AF: 0.0690 AC: 266

ESP6500AA AF: 0.0325 AC: 143

ESP6500EA AF: 0.0679 AC: 584

ExAC AF: 0.132 AC: 16023

Asia WGS AF: 0.248 AC: 861 AN: 3478

EpiCase AF: 0.0654

EpiControl AF: 0.0645

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Jul 09, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not specified Benign:1

Mar 29, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency

Primary ciliary dyskinesia Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.48
BayesDel_addAF	Benign	-0.55	T
BayesDel_noAF	Benign	-0.42
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.15	T
Eigen	Pathogenic	0.70
Eigen_PC	Uncertain	0.65
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.77	T
MetaRNN	Benign	0.00065	T
MetaSVM	Benign	-0.92	T
MutationAssessor	Pathogenic	3.2	M
PhyloP100		2.4
PrimateAI	Uncertain	0.52	T
PROVEAN	Uncertain	-3.9	D
REVEL	Benign	0.18
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.0020	D
Polyphen		0.98	D
Vest4		0.24
MPC		0.39
ClinPred		0.040	T
GERP RS		5.0
Varity_R		0.46
gMVP		0.64
Mutation Taster		=96/4	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs12623642; hg19: chr2-26676395; COSMIC: COSV55501815; COSMIC: COSV55501815;