rs143181834

Positions:

• chr2-26440481-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_145038.5(DRC1):​c.992C>T​(p.Thr331Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00418 in 1,612,912 control chromosomes in the GnomAD database, including 36 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0074 (7 hom., cov: 32)
  • Exomes 𝑓: 0.0039 (29 hom.)
• Consequence: DRC1 NM_145038.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 2.94

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0047012568).
• BP6: Variant 2-26440481-C-T is Benign according to our data. Variant chr2-26440481-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 414289.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-26440481-C-T is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00738 (1122/152096) while in subpopulation AFR AF= 0.0191 (792/41484). AF 95% confidence interval is 0.018. There are 7 homozygotes in gnomad4. There are 525 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 7 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DRC1	NM_145038.5	c.992C>T	p.Thr331Ile	missense_variant	8/17	ENST00000288710.7	NP_659475.2
DRC1	XM_047446339.1	c.9-3741C>T		intron_variant			XP_047302295.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DRC1	ENST00000288710.7	c.992C>T	p.Thr331Ile	missense_variant	8/17	2	NM_145038.5	ENSP00000288710.2

Frequencies

GnomAD3 genomes AF: 0.00737 AC: 1120 AN: 151978 Hom.: 7 Cov.: 32

Gnomad AFR AF: 0.0191

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00236

Gnomad ASJ AF: 0.00779

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00704

Gnomad FIN AF: 0.000378

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00319

Gnomad OTH AF: 0.00527

GnomAD3 exomes AF: 0.00502 AC: 1260 AN: 251078 Hom.: 11 AF XY: 0.00491 AC XY: 667 AN XY: 135712

Gnomad AFR exome AF: 0.0195

Gnomad AMR exome AF: 0.00409

Gnomad ASJ exome AF: 0.00826

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00981

Gnomad FIN exome AF: 0.000508

Gnomad NFE exome AF: 0.00324

Gnomad OTH exome AF: 0.00669

GnomAD4 exome AF: 0.00385 AC: 5625 AN: 1460816 Hom.: 29 Cov.: 33 AF XY: 0.00396 AC XY: 2881 AN XY: 726738

Gnomad4 AFR exome AF: 0.0196

Gnomad4 AMR exome AF: 0.00392

Gnomad4 ASJ exome AF: 0.00958

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0104

Gnomad4 FIN exome AF: 0.000675

Gnomad4 NFE exome AF: 0.00295

Gnomad4 OTH exome AF: 0.00474

GnomAD4 genome AF: 0.00738 AC: 1122 AN: 152096 Hom.: 7 Cov.: 32 AF XY: 0.00706 AC XY: 525 AN XY: 74330

Gnomad4 AFR AF: 0.0191

Gnomad4 AMR AF: 0.00236

Gnomad4 ASJ AF: 0.00779

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00705

Gnomad4 FIN AF: 0.000378

Gnomad4 NFE AF: 0.00319

Gnomad4 OTH AF: 0.00522

Alfa AF: 0.00376 Hom.: 1

Bravo AF: 0.00836

TwinsUK AF: 0.00297 AC: 11

ALSPAC AF: 0.00363 AC: 14

ESP6500AA AF: 0.0207 AC: 91

ESP6500EA AF: 0.00267 AC: 23

ExAC AF: 0.00553 AC: 671

Asia WGS AF: 0.00404 AC: 15 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 19, 2024	See Variant Classification Assertion Criteria. -

Primary ciliary dyskinesia Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

- -

Primary ciliary dyskinesia 21 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

May 12, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_addAF	Benign	-0.53	T
BayesDel_noAF	Benign	-0.51
CADD	Benign	23
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.048	T
Eigen	Uncertain	0.56
Eigen_PC	Uncertain	0.48
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Benign	0.76	T
MetaRNN	Benign	0.0047	T
MetaSVM	Benign	-0.83	T
MutationAssessor	Pathogenic	3.1	M
PrimateAI	Uncertain	0.65	T
PROVEAN	Uncertain	-4.2	D
REVEL	Benign	0.14
Sift	Uncertain	0.0080	D
Sift4G	Benign	0.092	T
Polyphen		1.0	D
Vest4		0.27
MVP		0.35
MPC		0.14
ClinPred		0.021	T
GERP RS		4.3
Varity_R		0.16
gMVP		0.30

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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

Other links and lift over

dbSNP: rs143181834; hg19: chr2-26663349;